Inhibitors of 11β-hydroxysteroid dehydrogenase type 1

ABSTRACT

This invention relates to novel compounds of the Formula (I*), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.

RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/US2007/018789, filed Aug. 24, 2007, published in English, andclaims the benefit of U.S. Provisional Application No. 60/840,203, filedAug. 25, 2006, the entire teachings of which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to inhibitors of 11β-hydroxy steroiddehydrogenase type 1 (11β-HSD1); pharmaceutical compositions thereof andmethods of using the same.

BACKGROUND OF THE INVENTION

Glucocorticoids, such as cortisol (hydrocortisone), are steroid hormonesthat regulate fat metabolism, function and distribution, and play a rolein carbohydrate, protein and fat metabolism. Glucocorticoids are alsoknown to have physiological effects on development, neurobiology,inflammation, blood pressure, metabolism and programmed cell death.Cortisol and other corticosteroids bind both the glucocorticoid receptor(GR) and the mineralocorticoid receptor (MR), which are members of thenuclear hormone receptor superfamily and have been shown to mediatecortisol function in vivo. These receptors directly modulatetranscription via DNA-binding zinc finger domains and transcriptionalactivation domains.

Until recently, the major determinants of glucocorticoid action wereattributed to three primary factors: (1) circulating levels ofglucocorticoid (driven primarily by the hypothalamic-pituitary-adrenal(HPA) axis); (2) protein binding of glucocorticoids in circulation; and(3) intracellular receptor density inside target tissues. Recently, afourth determinant of glucocorticoid function has been identified:tissue-specific pre-receptor metabolism by glucocorticoid-activating and-inactivating enzymes. These 11β-hydroxysteroid dehydrogenase (11β-HSD)pre-receptor control enzymes modulate activation of GR and MR byregulation of glucocorticoid hormones. To date, two distinct isozymes of11-beta-HSD have been cloned and characterized: 11β-HSD1 (also known as11-beta-HSD type 1, 11betaHSD1, HSD11B1, and HSD11L) and 11β-HSD2.11β-HSD1 is a bi-directional oxidoreductase that regenerates activecortisol from inactive 11-keto forms, whereas 11β-HSD2 is aunidirectional dehydrogenase that inactivates biologically activecortisol by converting it into cortisone.

The two isoforms are expressed in a distinct tissue-specific fashion,consistent with the differences in their physiological roles. 11β-HSD1is widely distributed in rat and human tissues; expression of the enzymeand corresponding mRNA have been detected in human liver, adiposetissue, lung, testis, bone and ciliary epithelium. In adipose tissue,increased cortisol concentrations stimulate adipocyte differentiationand may play a role in promoting visceral obesity. In the eye, 11β-HSD1may regulate intraocular pressure and may contribute to glaucoma; somedata suggests that inhibition of 11β-HSD1 may cause a drop inintraocular pressure in patients with intraocular hypertension(Kotelevtsev, et al., (1997), Proc. Nat'l Acad. Sci. USA94(26):14924-9). Although 11β-HSD1 catalyzes both11-beta-dehydrogenation and the reverse 11-oxoreduction reaction,11β-HSD1 acts predominantly as a NADPH-dependent oxoreductase in intactcells and tissues, catalyzing the formation of active cortisol frominert cortisone (Low, et al., (1994) J. Mol. Endocrin. 13: 167-174). Incontrast, 11β-HSD2 expression is found mainly in mineralocorticoidtarget tissues such as kidney (cortex and medulla), placenta, sigmoidand rectal colon, salivary gland and colonic epithelial cell lines.11β-HSD2 acts as an NAD-dependent dehydrogenase catalyzing theinactivation of cortisol to cortisone (Albiston, et al., (1994) Mol.Cell. Endocrin. 105: R11-R17), and has been shown to protect the MR fromglucocorticoid excess (e.g., high levels of receptor-active cortisol)(Blum, et al., (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-216).

Mutations in either the 11β-HSD1 or the 11β-HSD2 genes result in humanpathology. For example, individuals with mutations in 11β-HSD2 aredeficient in this cortisol-inactivation activity and, as a result,present with a syndrome of apparent mineralocorticoid excess (alsoreferred to as “SAME”) characterized by hypertension, hypokalemia, andsodium retention (Edwards, et al., (1988) Lancet 2: 986-989; Wilson, etal., (1998) Proc. Nat'l Acad. Sci. 95: 10200-10205). Similarly,mutations in 11β-HSD1 and in the gene encoding a co-localizedNADPH-generating enzyme, hexose 6-phosphate dehydrogenase (H6PD), canresult in cortisone reductase deficiency (CRD); these individualspresent with ACTH-mediated androgen excess (hirsutism, menstrualirregularity, hyperandrogenism), a phenotype resembling polycystic ovarysyndrome (PCOS) (Draper, et al., (2003) Nat. Genet. 34: 434-439).

Notably, disruption of homeostasis in the HPA axis by either deficientor excess secretion or action results in Cushing's syndrome or Addison'sdisease, respectively (Miller & Chrousos, Endocrinology and Metabolism(Felig & Frohman eds., McGraw-Hill: New York, 4^(th) Ed. (2001))387-524). Patients with Cushing's syndrome or receiving glucocorticoidtherapy develop reversible visceral fat obesity. The phenotype ofCushing's syndrome patients closely resembles that of Reaven's metabolicsyndrome (also known as Syndrome X or insulin resistance syndrome), thesymptoms of which include visceral obesity, glucose intolerance, insulinresistance, hypertension, type 2 diabetes and hyperlipidemia (Reaven,(1993) Ann. Rev. Med. 44, 121-131). Although the role of glucocorticoidsin human obesity is not fully characterized, there is mounting evidencethat 11β-HSD1 activity plays an important role in obesity and metabolicsyndrome (Bujalska, et al., (1997) Lancet 349: 1210-1213); (Livingstone,et al., (2000) Endocrinology 131, 560-563; Rask, et al., (2001) J. Clin.Endocrinol. Metab. 86, 1418-1421; Lindsay, et al., (2003) J. Clin.Endocrinol. Metab. 88: 2738-2744; Wake, et al., (2003) J. Clin.Endocrinol. Metab. 88, 3983-3988).

Data from studies in mouse transgenic models supports the hypothesisthat adipocyte 11β-HSD1 activity plays a central role in visceralobesity and metabolic syndrome (Alberts, et al., (2002) Diabetologia.45(11), 1526-32). Over-expression in adipose tissue of 110-HSD1 underthe control of the aP2 promoter in transgenic mice produced a phenotyperemarkably similar to human metabolic syndrome (Masuzaki, et al., (2001)Science 294, 2166-2170; Masuzaki, et al., (2003) J. Clinical Invest.112, 83-90). Moreover, the increased activity of 11β-HSD1 in these mice,is very similar to that observed in human obesity (Rask, et al., (2001)J. Clin. Endocrinol. Metab. 86, 1418-1421). In addition, data fromstudies with 11βHSD1-deficient mice produced by homologous recombinationdemonstrate that the loss of 11β-HSD1 leads to an increase in insulinsensitivity and glucose tolerance due to a tissue-specific deficiency inactive glucocorticoid levels (Kotelevstev, et al., (1997) Proc. Nat'lAcad. Sci. 94: 14924-14929; Morton, et al., (2001) J. Biol. Chem. 276,41293-41300; Morton, et al., (2004) Diabetes 53, 931-938).

The published data supports the hypothesis that increased expression of11β-HSD1 contributes to increased local conversion of cortisone tocortisol in adipose tissue and hence that 11β-HSD1 plays a role in thepathogenesis of central obesity and the appearance of the metabolicsyndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17).Therefore, 11β-HSD1 is a promising pharmaceutical target for thetreatment of the metabolic syndrome (Masuzaki, et al., (2003) Curr. DrugTargets Immune Endocr. Metabol. Disord. 3: 255-62). Furthermore,inhibition of 11β-HSD1 activity may prove beneficial in treatingnumerous glucocorticoid-related disorders. For example, 11β-HSD1inhibitors could be effective in combating obesity and/or other aspectsof the metabolic syndrome cluster, including glucose intolerance,insulin resistance, hyperglycemia, hypertension, and/or hyperlipidemia(Kotelevstev, et al., (1997) Proc. Nat'l Acad. Sci. 94, 14924-14929;Morton et al., (2001) J. Biol. Chem. 276, 41293-41300; Morton, et al.,(2004) Diabetes 53, 931-938). In addition, inhibition of 1113-HSD1activity may have beneficial effects on the pancreas, including theenhancement of glucose-stimulated insulin release (Billaudel & Sutter,(1979) Horm. Metab. Res. 11, 555-560; Ogawa, et al., (1992) J. Clin.Invest. 90, 497-504; Davani, et al., (2000) J. Biol. Chem. 275,34841-34844). Inter-individual differences in general cognitive functionhas been linked to variability in the long-term exposure toglucocorticoids (Lupien, et al., (1998) Nat. Neurosci. 1: 69-73) anddysregulation of the HPA axis. Such chronic exposure to glucocorticoidexcess in certain brain subregions has been theorized to contribute tothe decline of cognitive function (McEwen & Sapolsky (1995) Curr. Opin.Neurobiol. 5, 205-216). Therefore, inhibition of 11β-HSD1 may reduceexposure to glucocorticoids in the brain and thereby protect againstdeleterious glucocorticoid effects on neuronal function, includingcognitive impairment, dementia, and/or depression.

There is also evidence that glucocorticoids and 11β-HSD1 play a role inregulation of in intra-ocular pressure (IOP) (Stokes et al., (2000)Invest. Opthalmol. Vis. Sci. 41: 1629-1683; Rauz, et al., (2001) Invest.Opthalmol. Vis. Sci. 42: 2037-2042). If left untreated, elevated IOP canlead to partial visual field loss and eventually blindness. Thus,inhibition of 11β-HSD1 in the eye could reduce local glucocorticoidconcentrations and IOP, and hence could be used to treat or preventglaucoma and other visual disorders.

Transgenic aP2-11β-HSD1 mice exhibit high arterial blood pressure andhave increased sensitivity to dietary salt. Additionally, plasmaangiotensinogen levels are elevated in the transgenic mice, as areangiotensin II and aldosterone. Treatment of the mice with anangiotensin II antagonist alleviates the hypertension (Masuzaki, et al.,(2003) J. Clinical Invest. 112, 83-90). This suggests that hypertensionmay be caused or exacerbated by 11β-HSD1 activity. Thus, 11β-HSD1inhibitors may be useful for treatment of hypertension andhypertension-related cardiovascular disorders.

Glucocorticoids can have adverse effects on skeletal tissues, andprolonged exposure to even moderate glucocorticoid doses can result inosteoporosis (Cannalis, (1996) J. Clin. Endocrinol. Metab. 81,3441-3447). In addition, 11β-HSD1 has been shown to be present incultures of human primary osteoblasts as well as cells from adult bone(Cooper, et al., (2000) Bone 27: 375-381), and the 11β-HSD1 inhibitorcarbenoxolone has been shown to attenuate the negative effects ofglucocorticoids on bone nodule formation (Bellows, et al., (1998) Bone23: 119-125). Thus, inhibition of 11β-HSD1 is predicted to decrease thelocal glucocorticoid concentration within osteoblasts and osteoclasts,thereby producing beneficial effects in various forms of bone disease,including osteoporosis.

As evidenced herein, there is a continuing need for new and improveddrugs that inhibit 11β-HSD1. The novel compounds of the presentinvention are effective inhibitors of 11β-HSD1.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I*:

wherein:

K, L, M, X and Y are independently C, N or O, provided that the totalnumber of nitrogen and oxygen atoms in the ring is 3 or leis and when K,L, M, X or Y is O, any adjacent member atom in the ring cannot be O;

the bonds between K, L, M, X and Y are single or double bonds providedthat no consecutive double occur between member atoms of the ring;

n=0, 1, or 2;

s=1 or 2;

t=1 or 2;

R¹-R⁵ are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl),A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶,A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl,alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl,wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R¹-R⁵ are optionally and independently substitutedwith 1-3 groups independently selected from the group consisting ofhalogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶;

when K, L, M, X, or Y is (—O—) or (—N═), then p1; p2, p3, p4 or p5,respectively, is 0; when K, L, M, X, or Y is (—N—), (—C═), or (—CH—),then p1, p2, p3, p4 or p5, respectively, is 1; when K, L, M, X or Y is(—C—), then p1, p2, p3, p4 or p5, respectively, is 2; and when K, L, M,X, or Y is (—C—), and R¹, R², R³, R⁴ or R⁵ is connected through a doublebond to K, L, M, X or Y, respectively, then p1, p2, p3, p4 or p5,respectively, is 1;

A is a single bond, (C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₅)alkylCH═,C(O)(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkylene,C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene, S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶;

R¹, K, L and R² are taken together to form a fused benzene or pyridinering, which is optionally substituted with 1-3 groups independentlyselected from the group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or

R², L, M and R³ are taken together to form a fused benzene or pyridinering, which is optionally substituted with 1-3 groups independentlyselected from the group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or

R², L, X and R⁴ are taken together, when n=0, to form a fused benzene orpyridine ring, which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, hydroxy,cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶, provided that n=0 and Mand R³ are absent; or

R⁴, X, Y and R⁵ are taken together to form a fused benzene or pyridinering, which is optionally substituted with 1-3 groups independentlyselected from the group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or

the group consisting of R¹, K, L and R² and the group consisting of R⁴,X, Y and R⁵ are each taken together to form a fused benzene or pyridinering, each of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, hydroxy,cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,(R⁶)₂N(C₁-C₁₀)alkyl, aryl or arylalkyl, wherein the aryl and arylalkylgroups are optionally substituted with up to three groups independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or

N(R⁶)₂ is a heterocyclyl group containing at least one nitrogen atom,preferably selected from W¹-W⁷:

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₇ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof;

optionally, with the general provisos that:

(1) if R¹, K, L and R² form a fused benzene or pyridine ring, Q is NR⁶,R⁶ is H, Y is O, s=1, t=2, n=6, X is C, R⁴ is H and R⁵ is absent, thenR⁷ is not a 7- to 10-membered carbocyclic group or heterocyclic group;

(2) if R¹, K, L and R² form a fused benzene ring, Q is NR⁶, R⁶ is H,n=1, s=1, t=1 or 2, and M, X and Y are all carbon, then at least one ofR³, R⁴ or R⁵ must not be —(CH₂)_(n)—Z, wherein n=0 to 2, and Z ishydrogen, (C₁-C₆)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substitutedor unsubstituted phenyl wherein if the phenyl is substituted, there are1 or 2 substituents independently selected from the group consisting ofhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, carboxyl, cyano, loweralkylthio,carboxy-loweralkyl, nitro, —CF₃ or hydroxy. Preferably, if R¹, K, L andR² form a fused benzene ring, Q is NR⁶, R⁶ is H, n=1, s=1, t=1 or 2, andM, X and Y are all carbon, then at least one of R³, R⁴ or R⁵ must not be—(CH₂)_(n)—Z, wherein n=0 to 2, and Z is hydrogen, C₁-C₆ alkyl,2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl;and

(3) if R¹, K, L and R² form a fused benzene ring, Q is NR⁶, R⁶ is H,n=0, s=1, t=1 or 2, X is C or O and Y is C or O, then at least one of R⁴or R⁵ must not be —CH₂)_(n)—Z, wherein n=0 to 2, and Z is hydrogen,(C₁-C₆)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted orunsubstituted phenyl wherein if the phenyl is substituted, there are 1or 2 substituents independently selected from the group consisting ofhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, carboxyl, cyano, loweralkylthio,carboxy-loweralkyl, nitro, —CF₃ or hydroxy. Preferably, if R¹, K, L andR² form a fused benzene ring, Q is NR⁶, R⁶ is H, n=0, s=1, t=1 or 2, Xis C or O and Y is C or O, then at least one of R⁴ or R⁵ must not be—CH₂)_(n)—Z wherein n=0 to 2, and Z is hydrogen, (C₁-C₆)alkyl,2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl.

Additionally, embodiments of Formula I* can optionally have thefollowing provisos:

4) if R¹, K, L and R² form a fused benzene ring; Q is O or NR⁶; R⁶ is H,phenyl, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or hydroxy(C₁-C₈)alkyl; s=1 or2; t=1 or 2; and 1) n is 0, X is C, and Y is N or 0, 2) n is 1, X is Nor O, Y is C, and M is C, or 3) n is 2, X is C, Y is C, and the M α tothe fused benzene is C and the M β to the fused benzene is N or O; thenR⁷ must not be C₇-C₁₂ bicycloalkyl or C₉-C₁₂ tricycloalkyl;

5) if R¹, K, L and R² form a fused benzene ring; R⁴ is H; R⁵ is H; Q isNH; s=1, t=2; n=0; X is C; Y is C; there is an optional double bondbetween X and Y; then R⁷ must not be substituted bicyclo[2.2.2]octane orsubstituted bicyclo[2.2.1]heptane;

6) if R¹, K, L and R² form a fused benzene or pyridine ring; X is N; Yis C; n=0, 1; M, when present, is C; s=1 or 2; t=1 or 2; Q is O or NR⁶;R⁶ is (C₁-C₆)alkyl; then R⁷ must not be (C₇-C₁₂)bicycloalkyl or(C₉-C₁₂)tricycloalkyl, wherein the bicycloalkyl and tricycloalkyl arecarbocycles; and

7) if R¹, K, L and R² form a fused benzene ring; t=1, 2; s=1, 2; Q=NR⁶;R⁶═H, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, phenyl orarylalkyl; and 1) n=0, X is C, N, or O, and Y is C; or 2) n=1; M is C,N, or O; X═C, and Y═C; then R⁷ must not be adamantyl, a bridged(C₆-C₈)bicycloalkyl or a (C₉-C₁₂)tricycloalkyl wherein one cycloalkyl ofthe tricycloalkyl moiety is fused to a bridged bicycloalkyl moiety.

It is understood that provisos 1-7 can be suitably applied to allembodiments of the invention described herein. It is further understoodthat, depending on the embodiment of the invention, one or more ofprovisos 1-7 (i.e., any combination of provisos) can optionally beincluded in the description of any embodiment. For example, provisos 4,5, 6, or 7 can be individually applied to any embodiment; provisos 4 and5, 4 and 6, or 4 and 7 can be applied in combination to any embodiment;provisos 5 and 6 or 5 and 7 can be applied in combination to anyembodiment; provisos 6 and 7 can be applied in combination to anyembodiment; provisos 4, 5 and 6 can be applied in combination to anyembodiment; provisos 4, 5 and 7 can be applied in combination to anyembodiment; provisos 4, 6 and 7 can be applied in combination to anyembodiment; provisos 5, 6 and 7 can be applied in combination to anyembodiment; or provisos 4, 5, 6 and 7 can be applied in combination toany embodiment.

Another embodiment of the invention is a compound of Formula I:

wherein:

K, L, M, X and Y are independently C, N or O, provided that the totalnumber of nitrogen and oxygen atoms in the ring is 3 or less and when K,L, M, X or Y is O, any adjacent member atom in the ring cannot be O;

the bonds between K, L, M, X and Y are single or double bonds providedthat no consecutive double bonds occur between member atoms of the ring;

n=0, 1, or 2;

s=1 or 2;

t=1 or 2;

R¹-R⁵ are independently hydrogen, A-(5-tetrazolyl), A-COOR⁶, A-CON(R⁶)₂,A-COR⁶, A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl, cycloalkyl,heteroaryl, aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, arylor arylalkyl groups represented by R¹-R⁵ are optionally andindependently substituted with 1-3 groups independently selected fromthe group consisting of halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,CONH₂ and NR⁶SO₂R⁶, except that any one or more of R¹-R⁵ is absent wherethe atom to which such R¹-R⁵ group would otherwise be connected is (i)O, or (ii) an N that is connected by a double bond to an adjacent atom;

A is a single bond, C(R⁶)₂ or C(R⁶)₂C(R⁶)₂;

R¹, K, L and R² are taken together to form a fused benzene or pyridinering, each of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂and NR⁶SO₂R⁶; or

R², L, M and R³ are taken together to form a fused benzene or pyridinering, each of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂and NR⁶SO₂R⁶; or

R², L, X and R⁴ are taken together, when n=0, to form a fused benzene orpyridine ring, each Of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂and NR⁶SO₂R⁶ provided that n=0 and M and R³ are absent; or

R⁴, X, Y and R⁵ are taken together to form a fused benzene or pyridinering, each of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂and NR⁶SO₂R⁶; or

the group consisting of R¹, K, L and R² and the group consisting of R⁴,X, Y and R⁵ are each taken together to form a fused benzene or pyridinering, each of which is optionally substituted with 1-3 groupsindependently selected from the group consisting of halogen, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂and NR⁶SO₂R⁶;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, aryl or arylalkyl;

Q is O or NR⁶;

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof;

with the general provisos that:

(1) if R¹, K, L and R² form a fused benzene or pyridine ring, Q is NR⁶,R⁶ is H, Y is O, s=1, t=2, n=0, X is C, R⁴ is H and R⁵ is absent, thenR⁷ is not a 7- to 10-membered carbocyclic group or heterocyclic group;

(2) if R¹, K, L and R² form a fused benzene ring, Q is NR⁶, R⁶ is H,n=1, s=t=1 or 2, and M, X and Y are all carbon, then at least one of R³,R⁴ or R⁵ must not be —(CH₂)_(n)—Z, wherein n=0 to 2, and Z is hydrogen,(C₁-C₆)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted orunsubstituted phenyl wherein if the phenyl is substituted, there are 1or 2 substituents independently selected from the group consisting ofhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, carboxyl, cyano, loweralkylthio,carboxyloweralkyl, nitro, —CF₃ or hydroxy. Preferably, if R¹, K, L andR² form a fused benzene ring, Q is NR⁶, R⁶ is H, n=1, s=1, t=1 or 2, andM, X and Y are all carbon, then at least one of R³, R⁴ or R⁵ must not be—(CH₂)—Z, wherein n=0 to 2, and Z is hydrogen, C₁-C₆ alkyl, 2-pyridyl,3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl; and

(3) if R¹, K, L and R² form a fused benzene ring, Q is NR⁶, R⁶ is H,n=0, s=1, t=1 or 2, X is C or O and Y is C or O, then at least one of R⁴or R⁵ must not be —(CH₂)_(n)—Z, wherein n=0 to 2, and Z is hydrogen,(C₁-C₆)alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or substituted orunsubstituted phenyl wherein if the phenyl is substituted, there are 1or 2 substituents independently selected from the group consisting ofhalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, carboxyl, cyano, loweralkylthio,carboxyloweralkyl, nitro, —CF₃ or hydroxy. Preferably, if R¹, K, L andR² form a fused benzene ring, Q is NR⁶, R⁶ is H, n=0, s=1, t=1 or 2, Xis C or O and Y is C or O, then at least one of R⁴ or R⁵ must not be—CH₂)_(n)—Z wherein n=0 to 2, and Z is hydrogen, (C₁-C₆)alkyl,2-pyridyl, 3-pyridyl, 4-pyridyl or substituted or unsubstituted phenyl.

Additionally, embodiments of Formula I can optionally have the followingprovisos:

4) if R¹, K, L and R² form a fused benzene ring; Q is O or NR⁶; R⁶ is H,phenyl, (C₁-C₈)alkyl, halo(C₁-C₈)alkyl, or hydroxy(C₁-C₈)alkyl; s=1 or2; t=1 or 2; and 1) n is 0, X is C, And Y is N or 0, 2) n is 1, X is Nor O, Y is C, and M is C, or 3) n is 2, X is C, Y is C, and the M α tothe fused benzene is C and the M β to the fused benzene is N or O; thenR⁷ must not be C₇-C₁₂ bicycloalkyl or C₉-C₁₂ tricycloalkyl;

5) if R¹, K, L and R² form a fused benzene ring; R⁴ is H; R⁵ is H; Q isNH; s=1, t=2; n=0; X is C; Y is C; there is an optional double bondbetween X and Y; then R⁷ must not be substituted bicyclo[2.2.2]octane orsubstituted bicyclo[2.2.1]heptane;

6) if R¹, K, L and R² form a fused benzene or pyridine ring; X is N; Yis C; n=0, 1; M, when present, is C; s=1 or 2; t=1 or 2; Q is O or NR⁶;R⁶ is (C₁-C₆)alkyl; then R⁷ must not be (C₇-C₁₂)bicycloalkyl or(C₉-C₁₂)tricycloalkyl, wherein the bicycloalkyl and tricycloalkyl arecarbocycles; and

7) if R¹, K, L and R² form a fused benzene ring; t=1, 2; s=1, 2; Q=NR⁶;R⁶═H, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, phenyl orarylalkyl; and 1) n=0, X is C, N, or O, and Y is C; or 2) n=1; M is C,N, or O; X═C, and Y═C; then R⁷ must not be adamantyl, a bridged(C₆-C₈)bicycloalkyl or a (C₉-C₁₂)tricycloalkyl wherein one cycloalkyl ofthe tricycloalkyl moiety is fused to a bridged bicycloalkyl moiety.

Preferred compounds of the invention are those of any embodiment ofFormulae I* or I where none of K, L, M, X, and Y is a basic N, and theremainder of the variables are defined above.

Also preferred are compounds of any embodiment of Formulae I* or I whereR¹, K, L and R² form a fused benzene ring, and the remainder of thevariables are defined above.

Additionally compounds of the invention are those of any embodiment ofFormulae I* or I wherein K, L, M, X, and Y are individually C or O;R¹-R⁵ are independently H or alkyl; and/or the bonds between K, L, M, X,and Y are all single bonds, and the remainder of the variables aredefined above.

Other compounds of the invention are those of any embodiment of FormulaI* or I, wherein Q is O or NH, and the remainder of the variables aredefined above.

Other preferred compounds of the invention are those of Formula I* or Iwherein Q is NR⁶ or O, R⁶ is H and/or R⁷ is 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-(methylsulfonyl)-4-adamantyl,1-(aminosulfonyl)-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl, and the remainder of the variablesare defined above.

Other preferred compounds are those of Formula I* or I, wherein Q is Oand/or R⁷ is selected from the group consisting of 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl, and1-carbamoyl-4-adamantyl, and the remainder of the variables are definedabove.

Also preferred compounds are those of Formula I* or I, wherein n is 0, sis 1, and/or t is 2, and the remainder of the variables are definedabove.

Specific Examples of Compounds of the Invention Are

-   tert-Butyl    1′-(2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate;-   N-(2-Adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide;-   (±)-2-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-Methyl    2-(1′(2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (R)-Methyl    2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (S)-Methyl    2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   2-(1′-(2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer B;-   1-Acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide;-   1′-((2-Adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylic    acid;-   (±)-1′-(2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylic    acid;-   (±)-1′-(2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylic    acid;-   Ethyl    1′-(2-adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylate;-   (±)-Ethyl    1′-(cyclohexylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylate;-   N-(2-Adamantyl)-1-(methylsulfonyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide;-   2-adamantyl spiro[indoline-3,4′-piperidine]-1′-carboxylate;-   2-adamantyl 5-fluorospiro[indoline-3,4′-piperidine]-1′-carboxylate;-   2-adamantyl 5-methylspiro[indoline-3,4′piperidine]-1′-carboxylate;-   2-adamantyl 1-acetylspiro[indoline-3,4′-piperidine]-1′-carboxylate;-   (±)-2-adamantyl    3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;-   (±)-2-(1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid; and-   (±)-2-adamantyl    3(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;    or an enantiomer, diastereomer, geometrical isomer or    pharmaceutically acceptable salt thereof.

Additional Examples of Compounds of the Invention Are

-   2-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   N-(2-adamantyl)-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   tert-butyl    1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate;-   N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide;-   2-acetyl-N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide;-   ethyl    3-(1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)propanoate;-   3-(1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)propanoic    acid;-   N-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide;-   N1′-(2-adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide;-   ethyl    1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate;-   2-tert-butyl 1′-(2-adamantyl)    1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxylate;-   2-adamantyl    2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate;-   2-adamantyl    2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate;-   2-adamantyl    2-(isopropylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate;-   2-adamantyl    2-(5-cyanopyridin-2-yl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate;-   (±)-ethyl    2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-((7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 1;-   2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 2;-   (±)-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   (±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   (±)-3-((1H-tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   (±)-ethyl    2-(1′-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-ethyl    2-(1′-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydro    spiro[indene-1,4′-piperidine]-3-yl)acetic acid;-   (±)-ethyl    2-(1′-((2-adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-ethyl    2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-ethyl    2-(1′-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,42-piperidine]-3-yl)acetate;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-6-methoxy-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(1′-((2-adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-ethyl 2-(7-bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydro    spiro[indene-1,4′-piperidine]-3-yl)acetate;-   (±)-2-(7-bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 1;-   2-(7-bromo-1′((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 2;-   (±)-2-(6-methyl-1′42-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-2-(5-methyl-1′((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′42-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoic    acid;-   (±)-ethyl    2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate;-   (±)-2-(7-bromo-1′42-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoic    acid;-   (±)-2-adamantyl    7-bromo-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;-   (±)-7-bromo-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   (±)-2-adamantyl    3-(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;-   2-(1′-((1-carbamoyl-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 1;-   2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    Acid, isomer 2;-   2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3′-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 3;-   2-(7-bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   2-(7-bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 1;-   2-(7-bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 2;-   2-(7-bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid, isomer 3;-   (±)-2-(7-bromo-1′-(1,7-dihydroxy-4-adamantyl    carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   N-(2-adamantyl)-6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxamide;-   (2-adamantyl)    9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate;-   2-(3-((2-adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic    acid;-   methyl    2-(34(2-adamantyl)carbamoyl)-3-azaspiro[5,5]undecan-9-yl)acetate;-   2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetic    acid;-   N-(2-adamantyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide;-   2-adamantyl 3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate;-   1-tert-butyl    1′-(trans-1-carbamoyl-4-adamantyl)spiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate;-   N-(2-adamantyl)-2-methylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   7-Chloro-N-(2-adamantyl)-2-methylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   2-(1′-((1-(benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic    acid;-   (±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   1-tert-butyl    1′-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate;-   1-tert-butyl-1′-(2-adamantyl)    5-fluorospiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate;-   1-tert-butyl-1′-(2-adamantyl)    5-methylspiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate;-   (±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-1-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-1-hydroxy-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   N-(2-adamantyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide;-   7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide;    and-   7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide;    or an enantiomer, diastereomer, geometrical isomer or    pharmaceutically acceptable salt thereof.

Additional compounds of the invention are those of Formula Ia:

wherein:

M and X are C or N;

the bonds in the ring containing M and X are single or double bondsprovided no consecutive double bonds occur between the member atoms ofthe ring;

n=0, or 1;

s=1;

t=1 or 2;

R¹-R⁵ are independently hydrogen, COOR⁶, CH₂COOR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, COR^(E), SO₂R⁶, CONHSO₂R⁶, CH₂CONHSO₂R⁶, alkyl, cycloalkyl,heteroaryl, aryl or arylalkyl wherein the cycloalkyl, heteroaryl, arylor arylalkyl groups represented by R¹-R⁵ are optionally andindependently substituted with 1-3 groups independently selected fromthe group consisting of halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,CONH₂ and NR⁶SO₂R⁶, except that any one or more of R¹-R⁵ is absent wherethe atom to which such R¹-R⁵ group would otherwise be connected is (i)O, or (ii) an N that is connected by a double bond to an adjacent atom;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, aryl or arylalkyl;

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Preferred compounds of the invention are those of Formula Ia where Q isNR⁶ or O, R⁶ is H and/or R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-bicyclo[2.2.2]octyl, 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl, and theremainder of the variables are defined above.

Preferred compounds of the invention are those of Formula Ia where noneof K, L, M, X, and Y is a basic N, and the remainder of the variablesare defined above.

Additional compounds of the invention are those according to FormulaIa′:

wherein:

M and X are C or N; the bonds in the ring containing M and X are singleor double bonds provided no consecutive double bonds occur between themember atoms of the ring;

n=0, or 1;

s=1;

t=1 or 2;

R¹-R⁵ are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl),A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶,A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, alkyl, alkenyl,cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl, wherein thealkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R¹-R⁵ are optionally and independently substitutedwith 1-3 groups independently selected from the group consisting ofhalogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶;

when K, L, M, X, or Y is (—O—) or (—N═), then p1, p2, p3, p4 or p5,respectively, is 0; when K, L, M, X, or Y is (—N—), (—C═), or (—CH—),then p1, p2, p3, p4 or p5, respectively, is 1; when K, L, M, X or Y is(—C—), then p1, p2, p3, p4 or p5, respectively, is 2; and when K, L, M,X, or Y is (—C—), and R¹, R², R³, R⁴ or R⁵ is connected through a doublebond to K, L, M, X or Y, respectively, then p1, p2, p3, p4 or p5,respectively, is 1;

A is a single bond, (C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₅)alkylCH═,C(O)(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkylene,C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene, S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,(R⁶)₂N(C₁-C₁₀)alkyl, aryl or arylalkyl, wherein the aryl and arylalkylgroups are optionally substituted with up to three groups independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or

N(R⁶)₂ is a heterocyclyl group containing at least one nitrogen atom,preferably selected from W¹-W⁷:

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Other particular compounds of the invention are according to Formula Ib:

wherein:

X and K are C, N or O;

s=1;

t=1 or 2;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, cyano, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂ and NR⁶SO₂R⁶;

R¹, R⁴ and R⁵ is independently H, COOR⁶, CH₂COOR⁶, CON(R⁶)₂;CH₂CON(R⁶)₂, COR⁶, SO₂R⁶, CONHSO₂R⁶, CH₂CONHSO₂R⁶, alkyl, cycloalkyl,heteroaryl, aryl or arylalkyl wherein the cyclohexyl, heteroaryl, arylor arylalkyl groups represented by R¹ and R⁴-R⁵ are optionally andindependently substituted with 1-3 groups independently selected fromthe group consisting of halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,CONH₂ and NR⁶SO₂R⁶, except that R⁴ or R⁵ is absent where the atom towhich such R⁴ or R⁵ group would otherwise be connected is (i) O, or (ii)an N that is connected by a double bond to an adjacent atom;

R⁶ is hydrogen, (C₁-C₄)alkyl, aryl or arylalkyl;

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Preferred compounds of the invention are those of Formula Do where Q isNR⁶ or O, R⁶ is H and/or R⁷ is 2-adamantyl, 1-hydroxy-4, adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-bicyclo[2.2.2]octyl, 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.

More particular compounds of the invention are those of Formula Ib′:

wherein X and K are C, N or O;

u=0, 1, 2 or 3;

n=0; or 1;

s=1;

t=1 or 2;

R¹, R⁴ and R⁵ are independently hydrogen, A-(5-tetrazolyl),A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶,A-CON(R⁶)₂, A-COR⁶, A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂,alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl,wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R¹, R⁴ and R⁵ are optionally and independentlysubstituted with 1-3 groups independently selected from the groupconsisting of halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CONH₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and—NR⁶SO₂OR⁶;

when K or X is (—O—) or (—N═), then p1 or p4, respectively, is 0; when Kor X is (—N—), (—C═), or (—CH—), then p1 or p4, respectively, is 1; whenK or X is (—C—), then p1 or p4, respectively, is 2; and when K or X is(—C—), and R¹ or R⁴ is connected through a double bond to K or X,respectively, then p1 or p4, respectively, is 1;

A is a single bond, (C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₅)alkylCH═,C(O)(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkylene,C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene, S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶;

R⁴, X, Y and R⁵ are taken together to form a fused benzene or pyridinering, which is optionally substituted with 1-3 groups independentlyselected from the group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C)—C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or

R⁶ is hydrogen, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,(R⁶)₂N(C₁-C₁₀)alkyl, aryl or arylalkyl, wherein the aryl and arylalkylgroups are optionally substituted with up to three groups independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or

N(R⁶)₂ is a heterocyclyl group containing at least one nitrogen atom,preferably selected from W¹-W⁷:

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₂₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Also preferred are compounds of the invention of Formula Ic:

wherein:

M, X and Y are independently C, N or O, provided that at least one ofthem is carbon and that when M, X, or Y is O, any adjacent member atomof the ring cannot be O;

the bonds between M and X and between X and Y are single or double bondsbut are not both simultaneously double bonds;

n=0, 1 or 2;

s=1;

t=1 or 2;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, cyano, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂ and NR⁶SO₂R⁶;

R³, R⁴ and R⁵ are independently H, COOR⁶, CH₂COOR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, COR⁶, SO₂R⁶, CONHSO₂R⁶, CH₂CONHSO₂R⁶, alkyl, cycloalkyl,heteroaryl, aryl or arylalkyl, wherein the cyclohexyl, heteroaryl, arylor arylalkyl groups represented by R³-R⁵ are optionally andindependently substituted with 1-3 groups independently selected fromthe group consisting of halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,CONH₂ and NR⁶SO₂R⁶, except that R⁴ or R⁵ is absent where the atom towhich such R⁴ or R⁵ group would otherwise be connected is (i) O, or (ii)an N that is connected by a double bond to an adjacent atom;

R⁶ is hydrogen, (C₁-C₄)alkyl, aryl or arylalkyl;

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶; NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Preferred compounds of the invention are those of Formula Ic wherein:n=0; X═C or N; Y═C; the bonds between M and X and between X and Y aresingle bonds; s=1 and t=2; R⁴ is H, COOR⁶ or CH₂COOR⁶; R⁵ is H; R⁶ ishydrogen or (C₁-C₄)alkyl; Q is O, NH or NR⁶; and/or R⁷ is 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl, and the remaining variables are asdefined for Formula Ic.

Also preferred are compounds of Formula Ic where Q is NR⁶ or O, R⁶ is Hand/or R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl or 1-carbamoyl-4-adamantyl, and theremaining variables are as defined for Formula Ic.

An additional embodiment of the invention is a compound of Formula Ic′:

wherein M, X and Y are independently C, N or O, provided that at leastone of them is carbon and that when M, X, or Y is O, any adjacent memberatom of the ring cannot be O;

0, 1, or 2;

s=1 or 2;

t=1 or 2;

u=0, 1, 2 or 3;

R³-R⁵ are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl),A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶,A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl,alkenyl, cycloalkyl, heteroaryl, heterocyclyl; aryl or arylalkyl,wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R³-R⁵ are optionally and independently substitutedwith 1-3 groups independently selected from the group consisting ofhalogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶;

when M, X, or Y is (—O—) or (—N═), then p3, p4 or p5, respectively, is0; when M, X, or Y is (—N—), (—C═), or (—CH—), then p3, p4 or p5,respectively, is 1; when M, X or Y is (—C—), then p3, p4 or p5,respectively, is 2; and when M, X or Y is (—C—), and R³, R⁴ or R⁵ isconnected through a double bond to M, X or Y, respectively, then p3, p4or p5, respectively, is 1;

A is a single bond, (C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₅)alkylCH═,C(O)(C₀-C₃)alkyl(C₃-C₆)Cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkylene,C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene, S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶;

R⁴, X, Y and R⁵ are taken together to form a fused benzene or pyridinering, which is optionally substituted with 1-3 groups independentlyselected from the group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,(R⁶)₂N(C₁-C₁₀)alkyl, aryl or arylalkyl, wherein the aryl and arylalkylgroups are optionally substituted with up to three groups independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or

N(R⁶)₂ is a heterocyclyl group containing at least one nitrogen atom,preferably selected from W¹-W⁷:

Q is O or NR⁶;

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxy(C₁-C₆)alkyl, C(═NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; and

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)_(alkyl), halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical, isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula Ic′ wherein:n=0; X═C or N; Y═C; the bonds between M and X and between X and Y aresingle bonds; s=1 and t=2; R⁴ is H, COOR⁶ or CH₂COOR⁶; R⁵ is H; R⁶ ishydrogen or (C₁-C₄)alkyl; Q is O, NH or NR⁶; and/or R⁷ is 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl, and the remaining variables are asdescribed for Formula Ic′.

Also preferred are compounds of Formula Ic′ where Q is NR⁶ or O, R⁶ is Hand/or R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl or 1-carbamoyl-4-adamantyl, and theremaining variables are as described for Formula Ic′.

Also preferred are compounds of the invention of Formula Id:

wherein:

K and Y are independently C, N or O;

s=1;

t=1 or 2;

R¹ and R⁵ are independently H, COOR⁶, CH₂COOR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂,COR⁶, SO₂R⁶, CONHSO₂R⁶, CH₂CONHSO₂R⁶, alkyl, cycloalkyl, heteroaryl,aryl or arylalkyl, wherein the cycloalkyl, heteroaryl, aryl or arylalkylgroups represented by R¹ and R⁵ are optionally and independentlysubstituted with 1-3 groups independently selected from the groupconsisting of halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, CONH₂ andNR⁶SO₂R⁶, except that R¹ or R⁵ is absent where the atom to which such R¹or R⁵ group would otherwise be connected is (i) O, or (ii) an N that isconnected by a double bond to an adjacent atom;

R⁶ is hydrogen, (C₁-C₄)alkyl, aryl or arylalkyl;

Q is O or NR⁶;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, cyano, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(6-C₆)alkoxy, CONH₂ and NR⁶SO₂R⁶;and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 1-2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl; oxo-substituted heterocyclyl, halogen,hydroxy, hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶; NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Preferred compounds of the invention are those of Formula Id where Q isNR⁶ or O; R⁶ is H; and/or R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-bicyclo[2.2.2]octyl, 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl.

Further compounds of the invention are those according to Formula Id′:

wherein:

K and Y are independently C, N or O;

s=1;

t=1 or 2;

R¹ and R⁵ are independently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl),A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶,A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl,alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl or arylalkyl,wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R¹ and R⁵ are optionally and independentlysubstituted with 1-3 groups independently selected from the groupconsisting of halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CONH₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and—NR⁶SO₂OR⁶;

when K or Y is (—O—) or (—N═), then p1 or p5, respectively, is 0; when Kor Y is (—N—), (—C═), or (—CH—), then p1 or p5, respectively, is 1; whenK or Y is (—C—), then p1 or p5, respectively, is 2; and when K or Y is(—C—), and R¹ or R⁵ is connected through a double bond to K or Y,respectively, then p1 or p5, respectively, is 1;

A is a single bond, (C₁-C₆)alkylene, (C₁-C₆)alkenylene, (C₁-C₅)alkylCH═,C(O)(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkylene,C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene, S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkyl(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶;

R⁶ is hydrogen, (C₁-C₁₀)alkyl, halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl,(R⁶)₂N(C₁-C₁₀)alkyl, aryl or arylalkyl, wherein the aryl and arylalkylgroups are optionally substituted with up to three groups independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or

N(R⁶)₂ is a heterocyclyl group containing at least one nitrogen atom,preferably selected from W¹-W⁷:

Q is O or NR⁶; and

R⁷ is a saturated C₇-C₁₂ bicycloalkyl or saturated C₉-C₁₂ tricycloalkylin which 2 carbon atoms are optionally replaced with heteroatomsindependently selected from N and O, and which is optionally substitutedwith 1-3 substituents independently selected from the group consistingof R⁶, heteroaryl, oxo-substituted heteroaryl, amino-substitutedheteroaryl, heterocyclyl, oxo-substituted heterocyclyl, halogen,hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂,CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶,NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof:

Another particular embodiment of the invention are compounds of theformula:

wherein Q is O or NH; and/or R7 is 2-adamantyl, 1-hydroxy-4-adamantyl,1-(hydroxymethyl)-4-adamantyl, or 1-carbamoxyl-4-adamantyl; and the restof the variables are as described for Formula Id′; or an enantiomer,diastereomer, geometrical isomer or pharmaceutically acceptable saltthereof.

Also preferred are compounds of the invention of Formula Ie:

wherein R⁴, R⁷, Q, s and t are as defined for Formula I* above;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula Ie where R⁴ ishydrogen, A-(5-tetrazolyl), A-COOR⁶, ACON(R⁶)₂, A-CONHSO₂R⁶ or alkyl,where the alkyl represented by R⁴ is optionally substituted with 1-3groups independently selected from the group consisting of hydroxy,cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, —CONH₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and—NR⁶SO₂OR⁶; A is a bond or (C₁-C₃)alkylene; s=1; t=2; Q is NH or O; R⁷is 2-adamantyl, 1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-(methylsulfonyl)-4-adamantyl,1-(aminosulfonyl)-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl; 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl; u=1; and/or R⁸ is halogen or methyl;and the rest of the variables are as defined for Formula I* above.

Also preferred are compounds of the invention of Formula If:

wherein R⁴, R⁷, Q, s and t are as defined for Formula I above;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula If wherein R⁴is hydrogen, A-COOR⁶, A-COR⁶ or A-SO₂R⁶; A is a single bond,(C₁-C₆)alkylene, C(O)(C₁-C₆)alkylene, or S(O)₂(C₁-C₆)alkylene; s=1; t=2;Q is NH or O; R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-(methylsulfonyl)-4-adamantyl, 1-(aminosulfonyl)-4-adamantyl,1-bicyclo[2.2.2]octyl, 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; u=1; and/orR⁸ is halogen or methyl; and the rest of the variables are as definedfor Formula I* above.

Also preferred are compounds of the invention of Formula Ig:

wherein R⁴, R⁵, R⁷, Q, s and t are as defined for Formula I* above;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula Ig wherein R⁴and R⁵ are independently selected from hydrogen and (C₁-C₃)alkyl; s=1;t=2; Q is NH or O; R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-(methylsulfonyl)-4-adamantyl, 1-(aminosulfonyl)-4-adamantyl,1-bicyclo[2.2.2]octyl; 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; u=1; and/orR⁸ is halogen or methyl; and the rest of the variables are as definedfor Formula I* above.

Also preferred are compounds of the invention of Formula Ih:

wherein R⁵, R⁷, Q, s and t are as defined for Formula I* above;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula Ih where R⁵ ishydrogen or (C₁-C₃)alkyl; s=1; t=2; Q is NH or O; R⁷ is 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-(methylsulfonyl)-4-adamantyl,1-(aminosulfonyl)-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl; u=1; and/or R⁸ is halogen, methyl, ormethoxy; and the rest of the variables are as defined for Formula I*above.

Also preferred are compounds of the invention of Formula Ii:

wherein R⁴, R⁷, Q, s and t are as defined for Formula I* above;

u=0, 1, 2 or 3;

R⁸ is independently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.

Preferred compounds of the invention are those of Formula Ii where R⁴ isA-COOR⁶, A-CON(R⁶)₂, A-COR⁶, A-SO₂R⁶, or alkyl; A is a single bond,(C₁-C₆)alkylene, (C₁-C₆)alkenylene,C(O)(C₀-C₃)alkylene(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, C(O)(C₁-C₆)alkyleneor S(O)₂(C₁-C₆)alkylene, optionally substituted with up to 2(C₁-C₃)alkyl groups, and (ii) R⁶ and N(R⁶)₂ are as defined for Formula Iabove; s=1; t=2; Q is NH or O; R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl,1-hydroxymethyl-4-adamantyl, 1-carbamoyl-4-adamantyl,1-(methylsulfonyl)-4-adamantyl, 1-(aminosulfonyl)-4-adamantyl,1-bicyclo[2.2.2]octyl; 1-carbamoyl-4-bicyclo[2.2.2]octyl,9-bicyclo[3.3.1]nonyl or 3-carbamoyl-9-bicyclo[3.3.1]nonyl; u=1; and/orR⁸ is halogen or methyl; and the rest of the variables are as definedfor Formula I* above.

A further embodiment of the present invention is a compound according toformula Ij:

wherein: X¹ is:

and X² is NR¹⁰; or X¹ is CH₂, and X² is:

u=0, 1, 2, 3 or 4; R⁹ is oxo, hydroxy or thioxo; R¹⁰ is H, (C₁-C₆)alkyl,or substituted or unsubstituted arylalkyl; and R¹¹ is independentlyselected from halogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂,—NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂and —NR⁶SO₂OR⁶; or a pharmaceutically acceptable salt thereof.

A particular embodiment of Formula Ij is a compound wherein X² is NR¹⁰and X¹ is:

A more particular embodiment of Formula Ij is a compound wherein X¹ andX² are defined as in the preceding paragraph, R⁹ is thioxo and/or R¹⁰ isH, methyl or 4-methoxybenzyl.

An additional embodiment of Formula Ij is a compound, wherein X¹ is CH₂,and X² is:

A more particular embodiment of Formula Ij is a compound wherein X¹ andX² are defined in the preceding paragraph, R⁹ is oxo or hydroxy, and/oru is 1 and R¹¹ is halogen. More particularly, in one embodiment, R¹¹ ischloro.

A more particular embodiment of Formula Ij is a compound wherein X¹ andX² are defined in the preceding paragraph, R⁹ is oxo or hydroxy, and/oru is 0.

The present invention further provides a pharmaceutical compositioncomprising a disclosed 11β-HSD1 inhibitor, including a compound of theFormulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Iior Ij and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical compositioncomprising a disclosed 11β-HSD1 inhibitor, including a compound of theFormulae I, Ia, Ib, Ic, or Id and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating 11β-HSD1comprising administering to a mammal in need thereof an effective amountof a disclosed 11β-HSD1 inhibitor, including a compound of Formulae I*,I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij.

The present invention further provides methods of modulating 11β-HSD1 bycontacting 11β-HSD1 with a disclosed 11β-HSD1 inhibitor, including acompound of Formulae I, Ia, Ib, Ic, or Id.

The present invention further provides methods of inhibiting 11β-HSD1comprising administering to a mammal in need thereof an effective amountof a disclosed 11β-HSD1 inhibitor, including a compound of Formulae I,Ia, Ib, Ic or Id.

The present invention further provides methods of inhibiting 11β-HSD1comprising administering to a mammal in need thereof an effective amountof a disclosed 11β-HSD1 inhibitor, including a compound of Formulae I*,I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij.

The present invention further provides methods of inhibiting theconversion of cortisone to cortisol in a cell comprising administeringto a mammal in need thereof an effective amount of a compound ofFormulae I, Ia, Ib, Ic, or Id.

The present invention further provides methods of inhibiting theconversion of cortisone to cortisol in a cell comprising administeringto a mammal in need thereof an effective amount of a disclosed 11β-HSD1inhibitor, including a compound of Formulae I*, I, Ia, Ia′, Ib, Ic, Ic′,Id, Id′, Ie, If, Ig, Ih, Ii or Ij.

The present invention further provides methods of inhibiting productionof cortisol in a cell comprising administering to a mammal in needthereof an effective amount of a disclosed 11β-HSD1 inhibitor, includinga compound of Formulae I, Ia, Ib, Ic, or Id.

The present invention further provides methods of inhibiting productionof cortisol in a cell comprising administering to a mammal in needthereof an effective amount of a disclosed 11β-HSD1 inhibitor, includinga compound of Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie,If, Ig, Ih, Ii or Ij.

The present invention further provides methods of increasing insulinsensitivity comprising administering to a mammal in need thereof aneffective amount of a disclosed 11β-HSD1 inhibitor, including a compoundof Formulae I, Ia, Ib, Ic, or Id.

The present invention further provides methods of increasing insulinsensitivity comprising administering to a mammal in need thereof aneffective amount of a disclosed 11β-HSD1 inhibitor, including a compoundof Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih,Ii or Ij.

The present invention further provides methods of treating diseasesassociated with activity or expression of 11β-HSD1 comprisingadministering to a mammal in need thereof an effective amount of adisclosed 11β-HSD1 inhibitor, including a compound of Formulae I, Ia,Ib, Ic, or Id.

The present invention further provides methods of treating diseasesassociated with activity or expression of 11β-HSD1 comprisingadministering to a mammal in need thereof an effective amount of adisclosed 11β-HSD1 inhibitor, including a compound of Formulae I*, I,Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij.

Also included in the present invention is the use of a disclosed11β-HSD1 inhibitor, including a compound of Formulae I*, I, Ia, Ia′, Ib,Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij or a pharmaceuticallyacceptable salt thereof for the manufacture of a medicament, wherein thevalues for the variables are as described above for the pharmaceuticalcomposition of the invention. The medicament is for treating a diseaseor disorder related to the activity or expression of 11β-HSD1,inhibiting the conversion of cortisone to cortisol in a cell, inhibitingproduction of cortisol in a cell, increasing insulin sensitivity,modulating 11β-HSD1, and/or inhibiting 11β-HSD1.

Also included in the present invention is the use of a disclosed11β-HSD1 inhibitor, including a compound of Formulae I*, I, Ia, Ia′, Ib,Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij or a pharmaceuticallyacceptable salt thereof for therapy, such as treating a disease ordisorder related to the activity or expression of 11β-HSD1, inhibitingthe conversion of cortisone to cortisol in a cell, inhibiting productionof cortisol in a cell, increasing insulin sensitivity, modulating11β-HSD1, and/or inhibiting 11β-HSD1. Values for the variables of theFormulae are as described above.

Also included in the present invention is the use of a disclosed11β-HSD1 inhibitor, including a compound of Formulae I*, I, Ia, Ia′, Ib,Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij or a pharmaceuticallyacceptable salt thereof for treating a disease or disorder related tothe activity or expression of 11β-HSD1, inhibiting the conversion ofcortisone to cortisol in a cell, inhibiting production of cortisol in acell, increasing insulin sensitivity, modulating 11β-HSD1, and/orinhibiting 11β-HSD1. Values for the variables of the Formulae are asdescribed above.

DETAILED DESCRIPTION OF THE INVENTION Definitions

When any variable (e.g., aryl, heterocyclyl, R¹, R², etc.) occurs morethan once in a compound, its definition on each occurrence isindependent of any other occurrence.

The term “alkyl” means a straight or branched hydrocarbon radical having1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term “loweralkyl” means a C₁-C₇ straight or branched alkyl group.

“Alkylene” means a saturated aliphatic straight-chain divalenthydrocarbon radical having the specified number of carbon atoms, e.g.,—(CH₂)_(x)— wherein x is a positive integer such as 1-10, preferably1-6. Thus, “(C₁-C₆)alkylene” means a radical having from 1-6 carbonatoms in a linear or branched arrangement, with optional unsaturation oroptional substitution.

The term “cycloalkyl” means a saturated hydrocarbon ring having 3-8carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term “bicycloalkyl” means two saturated hydrocarbon rings having atotal of 7-12 carbon atoms which are joined by 1,1-fusion, 1,2-fusion or1,n-fusion to give spirocyclic ring systems, fused ring systems andbridged ring systems respectively. Spirocyclic ring systems include, forexample, spiro[2.4]heptane, spiro[2.5]octane, spiro[4.4]nonane,spiro[4.5]decane, spiro[5.5]undecane and the like. Fused ring systemsinclude, for example, bicyclo[4.1.0]heptane, octahydro-1H-indene,decahydronaphthalene and the like. Bridged ring systems include forexample, bicyclo[3.3.1]nonane, bicyclo[2.2.2]octane,bicyclo[2.2.1]heptane and the like.

The term “tricycloalkyl” means three saturated hydrocarbon ring having atotal of 9-12 carbon atoms which are joined by any combination of1,1-fusion, 1,2-fusion or 1,n-fusion and includes, for example,adamantyl, noradamantyl and the like.

The terms “alkoxy” and “alkylthio” are O-alkyl or S-alkyl, respectively,of 1-6 carbon atoms as defined above for “alkyl.”

The term “aryl” means an aromatic radical which is a phenyl group, aphenylalkyl group, a phenyl group substituted with 1-4 substituentsselected from alkyl as defined above, alkoxy as defined above, alkylthioas defined above, halogen, trifluoromethyl, dialkylamino as definedabove for alkyl, nitro, cyano, and N,N-dialkyl-substituted amido asdefined above for alkyl.

The term “heteroaryl” means a 5- and 6-membered heteroaromatic radicalwhich may optionally be fused to a ring containing 1-4 heteroatomsselected from N, O, and S and includes, for example, a heteroaromaticradical which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-,3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl,1H-benzimidazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-pyrazolyl,2-, 4-, or 5-imidazolyl and the like optionally substituted by asubstituent selected from alkyl as defined above, halogen, dialkylaminoas defined above for alkyl, nitro, cyano, and N,N-dialkyl substitutedamido as defined above for alkyl.

The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated orpartially unsaturated heterocyclic ring containing 1 to 4 heteroatomsindependently selected from N, O, and S, and include pyrrolidine,piperidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene,tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane,1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, morpholine,thiomorpholine, thiomorpholine 1,1-dioxide, tetrahydro-2H-1,2-thiazine1,1-dioxide, and isothiazolidine 1,1-dioxide.

The term “arylalkyl” means an aromatic radical attached to an alkylradical wherein aryl and alkyl are as defined above, for example,benzyl, phenethyl, and the like.

The term “adamantyl” means an adamantane moiety bonded to another atomvia the 1- or 2-position of adamantane.

The term “mammal” as used herein includes all mammals, including, butnot limited to, humans.

A “carbocyclic group” comprises at least one ring formed entirely bycarbon-carbon bonds. Such a group generally has from 1 to 3 fused orpendant rings, preferably one ring or two fused rings. Typically, eachring contains from 3 to 10 ring members, preferably from 5 to 8 ringmembers. Unless otherwise specified, such a ring may be aromatic ornon-aromatic. Representative examples of carbocyclic groups arecycloalkyl groups (e.g., cyclopentane and cyclohexane), cycloalkenes andcycloalkynes, as well as aromatic groups such as phenyl, benzyl,naphthyl, phenoxyl, benzoxyl and phenylethanonyl. Carbon atoms presentwithin a carbocyclic group may, of course, be further bonded to avariety of ring substituents, such as hydrogen, a halogen, cyano, nitro,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy, C₁-C₈alkylthio, hydroxy, amino, mono or di(C₁-C₈)alkylamino,(C₃-C₇)cycloalkyl(C₀-C₃)alkyl, halo(C₁-C₈)alkyl, halo(C₁-C₈)alkoxy,C₁-C₈ alkanoyl, C₁-C₈ alkoxycarbonyl, —COOH, —CONH₂, mono- ordi-(C₁-C₈)alkylcarboxamido, —SO₂NH₂, and mono ordi(C₁-C₈)alkylsulfonamido.

A “heterocyclic group” comprises at least one ring in which at least onering atom is a heteroatom (i.e., N, O or S), and the remainder of thering atoms are carbon. Preferably, a heterocyclic group comprises 1-4heteroatoms; within certain embodiments 1 or 2 heteroatoms is preferred.A heterocyclic group generally has from 1 to 3 fused or pendant rings,preferably one ring or two fused rings. Typically, each ring containsfrom 3 to 10 ring members, preferably from 5 to 8 ring members, and maybe optionally substituted with from 1 to 5 substituents such as halogen,cyano, nitro, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ alkoxy,C₁-C₈ alkylthio, hydroxy, amino, mono or di(C₁-C₈)alkyl amino,halo(C₁-C₈)alkyl, halo(C₁-C₈)alkoxy, hydroxy(C₁-C₈)alkyl,hydroxy(C₁-C₈)alkoxy, C₂-C₈ alkanoyl, C₁-C₈ alkoxycarbonyl, —COOH,—SO₂NH₂, mono or dialkylsulfonamido, —C(O)NH₂ or mono ordi(C₁-C₈)alkylcarboxamido. Unless otherwise specified, a heterocyclicgroup may be aromatic or nonaromatic. As with a carbocyclic group, atomswithin a heterocyclic ring may be further linked to a variety of ringsubstituents.

A heterocyclic ring may be attached to a pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. Preferably, if the total number of S andO atoms in the heterocycle exceeds 1, then these heteroatoms are notadjacent to one another. More preferably, the total number of S and Oatoms in the heterocycle is not more than 1.

Examples of heterocyclic groups include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, dithiazinyl, dihydrofurotetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, oxazolidinyl, oxazolyl,oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, thiadiazinyl, thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl and xanthenyl. It will beapparent that any such heterocyclic groups may be substituted with oneor more substituents as described above.

Preferred heterocyclic groups include, for example, pyridyl, pyrimidinyl(e.g., pyrimidin-2-yl), pyridinyl (pyridin-2-yl, pyridin-3-yl andpyridin-4-yl), morpholinyl (e.g., morpholin-4-yl), piperidinyl (e.g.,piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl), tetrazolyl,triazinyl, thienyl, coumarinyl, imidazolyl, oxazolyl, isoxazolyl,indolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, thiazolyl,benzothiadiazolyl, triazolyl, pyrazinyl, furyl, thienyl, benzothienyl,benzofuranyl, tetrahydropyranyl, tetrahydrofuranyl, indanyl, andsubstituted derivatives of the foregoing such asmethyl-tetrahydropyran-2-yl and 2-hydroxy-indan-1-yl.

The term “halogen” means fluorine, chlorine, iodine or bromine.

The term “basic nitrogen” refers to a nitrogen atom that is >50%protonated in aqueous solution at pH 7 and includes, for example, thenitrogen atoms dialkylamines and trialkylamines.

Compounds of Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If,Ig, Ih, and Ii may exist in various stereoisomeric or tautomeric forms.The invention encompasses all such forms, including active compounds inthe form of essentially pure enantiomers, racemic mixtures, andtautomers, including forms those not depicted structurally.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the salts ofthe compounds of the invention refer to non-toxic “pharmaceuticallyacceptable salts.” Pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide; calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,and triethiodide salts.

The compounds of the invention include pharmaceutically acceptableanionic salt forms, wherein the anionic salts include the acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylsulfate,mucate, napsylate, nitrate, pamoate, pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate,and triethiodide salts.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that solvates orhydrates of the compound or its pharmaceutically acceptable salts arealso included. “Solvates” refer to crystalline forms wherein solventmolecules are incorporated into the crystal lattice duringcrystallization. Solvate may include water or nonaqueous solvents suchas ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and EtOAc.Solvates, wherein water is the solvent molecule incorporated-into thecrystal lattice, are typically referred to as “hydrates”. Hydratesinclude stoichiometric hydrates as well as compositions containingvariable amounts of water.

When a disclosed compound or its pharmaceutically acceptable salt isnamed or depicted by structure, it is to be understood that thecompound, including solvates thereof, may exist in crystalline forms,non-crystalline forms or a mixture thereof. The compound or itspharmaceutically acceptable salts or solvates may also exhibitpolymorphism (i.e. the capacity to occur in different crystallineforms). These different crystalline forms are typically known as“polymorphs.” It is to be understood that when named or depicted bystructure, the disclosed compound and its pharmaceutically acceptablesalts, solvates or hydrates also include all polymorphs thereof.Polymorphs have the same chemical composition but differ in packing,geometrical arrangement, and other descriptive properties of thecrystalline solid state. Polymorphs, therefore, may have differentphysical properties such as shape, density, hardness, deformability,stability, and dissolution properties. Polymorphs typically exhibitdifferent melting points, IR spectra, and X-ray powder diffractionpatterns, which may be used for identification. One of ordinary skill inthe art will appreciate that different polymorphs may be produced, forexample, by changing or adjusting the conditions used in solidifying thecompound. For example, changes in temperature, pressure, or solvent mayresult in different polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The invention also includes various isomers and mixtures thereof.“Isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers).

Certain of the disclosed aspartic protease inhibitors may exist invarious stereoisomeric forms. Stereoisomers are compounds that differonly in their spatial arrangement. Enantiomers are pairs ofstereoisomers whose mirror images are not superimposable, most commonlybecause they contain an asymmetrically substituted carbon atom that actsas a chiral center. “Enantiomer” means one of a pair of molecules thatare mirror images of each other and are not superimposable.Diastereomers are stereoisomers that are not related as mirror images,most commonly because they contain two or more asymmetricallysubstituted carbon atoms. The symbol “*” in a structural formularepresents the presence of a chiral carbon center. “R” and “S” representthe configuration of substituents around one or more chiral carbonatoms. Thus, “R*” and “S*” denote the relative configurations ofsubstituents around one or more chiral carbon atoms. When a chiralcenter is not defined as R or S, a mixture of both configurations ispresent.

“Racemate” or “racemic mixture” means a compound of equimolar quantitiesof two enantiomers, wherein such mixtures exhibit no optical activity;i.e., they do not rotate the plane of polarized light.

“Geometric isomer” means isomers that differ in the orientation ofsubstituent atoms in relationship to a carbon-carbon double bond, to acycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H)on each side of a carbon-carbon double bond may be in an E (substituentsare on opposite sides of the carbon-carbon double bond) or Z(substituents are oriented on the same side) configuration.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include forming the salt of a freebase of each isomer of an isomeric pair using an optically active acid(followed by fractional crystallization and regeneration of the freebase), forming the salt of the acid form of each isomer of an isomericpair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

When a disclosed compound is named or depicted by structure withoutindicating the stereochemistry, and the compound has at least one chiralcenter, it is to be understood that the name or structure encompassesone enantiomer of inhibitor free from the corresponding optical isomer,a racemic mixture of the inhibitor and mixtures enriched in oneenantiomer relative to its corresponding optical isomer. Apharmaceutical composition of the invention may, alternatively or inaddition to a compound of Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id,Id′, Ie, If, Ig, Ih, Ii or Ij, comprise a pharmaceutically acceptablesalt of a compound of Formulae I*, I, la, Ia′, Ib, Ib′, Ic, Ic′, Id,Id′, Ie, If, Ig, Ih, Ii or Ij, or a prodrug or pharmaceutically activemetabolite of such a compound or salt and one or more pharmaceuticallyacceptable carriers therefor.

“Prodrug” means a pharmaceutically acceptable form of an effectivederivative of a compound (or a salt thereof) of the invention, whereinthe prodrug may be: 1) a relatively active precursor which converts invivo to a compound of the invention; 2) a relatively inactive precursorwhich converts in vivo to a compound of the invention; or 3) arelatively less active component of the compound that contributes totherapeutic activity after becoming available in vivo (i.e., as ametabolite). See “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

“Metabolite” means a pharmaceutically acceptable form of a metabolicderivative of a compound (or a salt thereof) of the invention, whereinthe derivative is an active compound that contributes to therapeuticactivity after becoming available in vivo.

“Effective amount” means that amount of active compound agent thatelicits the desired biological response in a subject. Such responseincludes alleviation of the symptoms of the disease or disorder beingtreated. The effective amount of a compound of the invention in such atherapeutic method is from about 10 mg/kg/day to about 0.01 mg/kg/day,preferably from about 0.5 mg/kg/day to 5 mg/kg/day.

“Inhibiting 11β-HSD1” means to decrease the activity of the 11β-HSD1enzyme.

“Modulating 11β-HSD1” means to impact the activity of the 11β-HSD1enzyme by altering its natural activity. Modulation can be analogous toinhibition when a disease or disorder relating to the activity 11β-HSD1would be effectively treated by suppressing the activity of the enzyme.

“Pharmaceutically acceptable carrier” means compounds and compositionsthat are of sufficient purity and quality for use in the formulation ofa composition of the invention and that, when appropriately administeredto an animal or human, do not produce an adverse reaction.

“Treatment” or “treating”, as used herein, refers to partially ortotally inhibiting, delaying, or reducing the severity of the disease ordisorder related to 11β-HSD1. The terms “treatment” and “treating” alsoencompass the prophylactic administration of a compound of the inventionto a subject susceptible to a disease or disorder related to theactivity or expression of 11β-HSD1 in an effort to reduce the likelihoodof a subject developing the disease or disorder, or slowing orpreventing progression of the disease. Prophylactic treatment includessuppression (partially or completely) of the disease or disorder, andfurther includes reducing the severity of the disease or disorder, ifonset occurs. Prophylactic treatment is particularly advantageous foradministration to mammals at risk for developing a disease or disorderrelated to 11β-HSD1.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Additionally, thecompounds of the present invention can be administered intranasally ortransdermally.

It will be obvious to those skilled in the art that the following dosageforms may comprise as the active ingredient, either compounds or acorresponding pharmaceutically acceptable salt of a compound of thepresent invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can either besolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersable granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier is a finely dividedsolid which is in a mixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from about one to aboutseventy percent of the active ingredient. Suitable carriers aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcelluose, a low melting wax, cocoa butter, and the like.Tablets, powders, cachets, lozenges, fast-melt strips, capsules andpills can be used as solid dosage forms containing the active ingredientsuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activeingredient is dispersed homogeneously therein, as by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, retentionenemas, and emulsions, for example, water or water propylene glycolsolutions. For parenteral injection, liquid preparations can beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared bydissolving the active ingredient in water and adding suitable colorants,flavors, stabilizing, and thickening agents as desired. Aqueoussuspensions for oral administration can be prepared by dispersing thefinely divided active ingredient in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. Insuch form, the composition is subdivided into unit doses containingappropriate quantities of the active ingredient. The unit dosage formcan be a packaged preparation, the package containing discretequantities of, for example, tablets, powders, and capsules in vials orampules. Also, the unit dosage form can be a tablet, cachet, capsule, orlozenge itself, or it can be the appropriate amount of any of these inpackaged form.

The quantity of active ingredient in a unit dose preparation may bevaried or adjusted from about 0.1 mg to about 1000.0 mg, preferably fromabout 0.1 mg to about 100 mg. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill inthe art. Also, the pharmaceutical composition may contain, if desired,other compatible therapeutic agents.

In therapeutic treatment or as a method-of-use as an inhibitor of11β-HSD1 or an inhibitor in the production of cortisol in the cell, theactive ingredient is preferably administered orally in a solid dosageform as disclosed above in an amount of about 0.1 mg to about 100 mg perdaily dose where the dose is administered once or more than once daily.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus, obesity, metabolic syndrome, insulin resistance,cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy,osteoporosis, glaucoma, Cushing's syndrome, depression, anxiety andAlzheimer's disease, cognitive decline (including age-related cognitivedecline), polycystic ovarian syndrome and infertility. In addition,compounds modulate the function of B and T cells of the immune system.

A pharmaceutical composition of the invention may, alternatively or inaddition to a compound of Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id,Id′, Ie, If, Ig, Ih, Ii or Ij, comprise a pharmaceutically acceptablesalt of a compound of Formulae I*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id,Id′, Ie, If, Ig, Ih, Ii or Ij, or a prodrug or pharmaceutically activemetabolite of such a compound or salt and one or more pharmaceuticallyacceptable carriers therefor.

The pharmaceutical compositions of the invention are 11β-HSD1inhibitors. Said compositions contain compounds having a mean inhibitionconstant (IC₅₀) against 11β-HSD1 of between about 1,000 nM to about0.001 nM; preferably between about 50 nM to about 0.001 nM; and morepreferably between about 5 nM to about 0.01 nM. The invention includes atherapeutic method for treating or ameliorating an 11β-HSD1 mediateddisorder in a subject in need thereof comprising administering to asubject in need thereof an effective amount of a compound of FormulaeI*, I, Ia, Ia′, Ib, Ib′, Ic, Ic′, Id, Id′, Ie, If, Ig, Ih, Ii or Ij, orthe enantiomers, diastereomers, or salts thereof or composition thereof.

The compounds of the invention are useful for ameliorating or treatingdisorders or diseases in which decreasing the level of cortisol iseffective in treating a disease state. Thus, the compounds of theinvention can be used in the treatment or prevention of diabetesmellitus, obesity, symptoms of metabolic syndrome, glucose intolerance,hyperglycemic, hypertension, hyperlipidemia, insulin resistance,cardiovascular disease, dyslipidernia, atherosclerosis, lipodystrophy,osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceralfat obesity associated with glucocorticoid therapy, depression, anxiety,Alzheimer's disease, dementia, cognitive decline (including age-relatedcognitive decline), polycystic ovarian syndrome and infertility. Inaddition, the compounds modulate the function of B and T cells of theimmune system and can therefore be used to treat diseases such astuberculosis, leprosy and psoriasis. They can also be used to promotewound healing, particularly in diabetic patients.

Additional diseases or disorders that are related to 11β-HSD1 activityinclude those selected from the group consisting of lipid disorders,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, vascular restenosis, pancreatitis, abdominal obesity,neurodegenerative disease, retinopathy, nephropathy, neuropathy,diabetes, coronary heart disease, stroke, peripheral vascular disease,Cushing's syndrome, hyperinsulinemia, viral diseases, and Syndrome X.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of Formula I or pharmaceutical composition thereofin a combination therapy with one or more additional agents for thetreatment of diabetes, dyslipidemia, cardiovascular disease,hypertension, obesity, cancer or glaucoma. Agents for the treatment ofdiabetes include insulins, such as Humulin® (Eli Lilly), Lantuse®(Sanofi Aventis), Novolin (Novo Nordisk), and Exubera® (Pfizer); PPARgamma agonists, such as Avandia® (rosiglitazone maleate, GSK) and Actos®(pioglitazone hydrochloride, Takeda/Eli Lilly); sulfonylureas, such asAmaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, SanofiAventis), Micronase®/Glynase® (glyburide, Pfizer), andGlucotrol®/Glucotrol XL® (glipizide, Pfizer); meglitinides, such asPrandin®/NovoNorm® (repaglinide, Novo Nordisk), Starlix® (nateglinide,Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such asGlucophase®/Glucophase XR® (metformin HCl, Bristol Myers Squibb) andGlumetza (metformin HCl, Depomed); thiazolidinediones; amylin analogs;GLP-1 analogs; DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck);PTB-1B inhibitors; protein kinase inhibitors (including AMP-activatedprotein kinase inhibitors); glucagon antagonists; glycogen synthasekinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogenphosphorylase inhibitors; sodium glucose co-transporter inhibitors, andα-glucosidase inhibitors, such as Precose®/Glucobay®/Prandase®/Glucor®(acarbose, Bayer) and Glyset® (miglitol, Pfizer). Agents for thetreatment of dyslipidemia and cardiovascular disease include statins,fibrates and ezetimibe. Agents for the treatment of hypertension includeα-blockers, β-blockers, calcium channel blockers, diuretics, angiotensinconverting enzyme (ACE) inhibitors, dual ACE and neutral endopeptidase(NEP) inhibitors, angiotensin-receptor blockers (ARBs), aldosteronesynthase inhibitor, aldosterone-receptor antagonists, or endothelinreceptor antagonist. Agents for the treatment of obesity includeorlistat, phentermine, sibutramine and rimonabant.

An embodiment of the invention includes administering an 11β-HSD1inhibiting compound of Formula I or composition thereof in a combinationtherapy with one or more other 11β-HSD1 inhibitors (whether suchinhibitors are also compounds of Formula I or are compounds of adifferent class/genus), or with combination products, such as Avandamet®(metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepirideand rosiglitazone maleate, GSK); Metaglip® (glipizide and metformin HCl,Bristol Myers Squibb); Janumet® (sitagliptin and metformin, Merck) andGlucovance® (glyburide and metformin HCl, Bristol Myers Squibb).

The following abbreviations have the indicated meanings:

Abbreviation Meaning BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthylBoc tert-butoxy carbonyl or t-butoxy carbonyl (Boc)₂O di-tert-butyldicarbonate Cbz Benzyloxycarbonyl CbzCl Benzyl chloroformate CDIcarbonyldiimidazole d day DAST diethylaminosulfur trifluoride DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N′-dicyclohexylcarbodiimide DCUN,N′-dicyclohexylurea DIAD diisopropyl azodicarboxylate DIBAL, DIBAHdiisobutylaluminum hydride DIEA N,N-diisopropylethylamine DMAP4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMPU1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone 2,4-DNP2,4-dinitrophenylhydrazine EDC•HCl1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride equivequivalents EtOAc ethyl acetate Fmoc1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]- Fmoc-OSu1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5- pyrrolidinedione HClhydrochloric acid HOBt 1-hydroxybenzotriazole HATU2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate HBTU2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphateHPLC high pressure-liquid chromatography KHMDS potassiumhexamethyldisilazane LAH or LiAlH₄ lithium aluminum hydride LC-MS liquidchromatography-mass spectroscopy LHMDS lithium hexamethyldisilazane MeCNacetonitrile MeOH methanol min minute MS mass spectrum MsClmethanesulfonyl chloride NaH sodium hydride NaHCO₃ sodium bicarbonateNaN₃ sodium azide NaOH sodium hydroxide Na₂SO₄ sodium sulfate NMMN-methylmorpholine NMP N-methylpyrrolidinone Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium(0) Pd(OAc)₂ Palladium(II)AcetatePd(OH)₂ PalladiumHydroxide PE petroleum ether PtO₂ Platinum Oxide quantquantitative yield rt room temperature satd saturated SOCl₂ thionylchloride SFC supercritical fluid chromatography SPA scintillationproximity assay SPE solid phase extraction TBS t-butyldimethylsilylTBSCl t-butyldimethylsilyl chloride TEA triethylamine or Et₃N TEMPO2,2,6,6-tetramethyl-1-piperidinyloxy free radical Teoc1-[2-(trimethylsilyl)ethoxycarbonyloxy]- Teoc-OSu1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin- 2,5-dione TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatographyTMS trimethylsilyl TMSCl chlorotrimethylsilane or trimethylsilylchloride t_(R) retention time TsOH p-toluenesulfonic acid

General Description of Synthesis

Compounds of Formulae I*, I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii and Ijcan be prepared by several processes. In the discussion below n, s, t,u, A, K, L, M, X, Y, Q and R¹-R^(8a) have the meanings indicated aboveunless otherwise noted. In cases where the synthetic intermediates andfinal products of Formulae I*, I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii orIj described below contain potentially reactive functional groups, forexample amino, hydroxyl, thiol and carboxylic acid groups, that mayinterfere with the desired reaction, it may be advantageous to employprotected forms of the intermediate. Methods for the selection,introduction and subsequent removal of protecting groups are well knownto those skilled in the art. (See, e.g., T. W. Greene & P. G. M. Wuts,“Protective Groups in Organic Synthesis” John Wiley & Sons, Inc., NewYork 1999). Such protecting group manipulations are assumed in thediscussion below and not described explicitly. Generally reagents in thereaction schemes are used in equimolar amounts; however, in certaincases it may be desirable to use an excess of one reagent to drive areaction to Completion. This is especially the case when the excessreagent can be readily removed by evaporation or extraction. Basesemployed to neutralize HCl in reaction mixtures are generally used inslight to substantial excess (1.05-5 equivalents).

In the first process of the invention a compound of Formula I or I*wherein Q=O is prepared by reaction of an amine of formula II with achloroformate of formula III in the presence of an organic or inorganicbase, for example N,N-diisopropylethylamine or K₂CO₃, in an inertsolvent such as CH₂Cl₂, MeCN or THF at −20° C. to 80° C., preferably 0°C. to 25° C. for between 0.5 h and 24 h.

Many spirocyclic amines of Formula II can be prepared by previouslydescribed routes or can be purchased. Tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate (Formula II wherein K, L,Y═C; X═N; R¹, K, L and R² form a fused benzene ring; n=0; s=1; t=2;=CO₂t-Bu; R⁵═H; R³ absent; single bonds from L to X and X to Y):

can be prepared from benzylspiro[indoline-3,4′-piperidine]-1′-carboxylate as disclosed in Example21 of U.S. Pat. No. 7,045,527, which is hereby incorporated byreference.

The following substituted tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate were purchased from WuXiPharmatech (Shanghai, China):

(±)-2-(2,3-Dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid(Formula II wherein K, L, X, Y═C; R¹, K, L and R² form a fused benzenering; n=0; s=1; t=2; R⁴═CH₂CO₂H; R⁵═H; R³ absent; single bonds from L toX and X to Y):

can be prepared by deprotection of2-(1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid as disclosed in Example 98 (Steps A and B) of U.S. Pat. No.5,578,593, which is hereby incorporated by reference.

The parent compound and the following substituted(±)-2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid werepurchased from WuXi Pharmatech (Shanghai, China) as their N-Boc or ethylester derivatives:

Ethyl 2-(7-bromospiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate waspurchased from WuXi Pharmatech (Shanghai, China):

2-(3-azaspiro[5.5]undecan-9-yl)acetic acid was purchased from WuXiPharmatech (Shanghai, China):

Tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (Formula II whereinK, L, X, Y═C; M=N; R¹, R², R⁴ and R⁵═H; n=1; s=1; t=2; R³=t-BuOCO;single bonds from K to L, L to M, M to X and X to Y):

can be prepared from 1-benzylpiperidin-4-one as disclosed in Example 1of U.S. Pat. No. 5,451,578, which is hereby incorporated by reference.This compound was purchased from WuXi Pharmatech (Shanghai, China).

Tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (Formula II whereinK, X, Y═C; L=N; n=0; s=1; t=2; R¹, R⁴ and R⁵═H; R²=t-BuOCO; single bondsfrom K to L, L to X and X to Y):

can be prepared from 8-benzyl-2-oxa-8-azaspiro[4.5]decane-1,3-dione asdisclosed in Example 19 (Steps A-G) of US Published Patent Application2003/055244, which is hereby incorporated by reference. This compoundwas purchased from WuXi Pharmatech (Shanghai, China).

Tert-Butyl 2,7-diazaspiro[4.5]decane-2-Carboxylate (Formula II whereinK, X, Y═C; L=N; n=0; s=2; t=1; R¹, R⁴ and R⁵═H; R³=t-BuOCO; single bondsfrom K to L, L to X and X to Y):

was purchased from WuXi Pharmatech (Shanghai, China) (catalog numberSA-008).

2,3-Dihydrospiro[indene-1,4′-piperidine] (Formula II wherein K, L, X,Y═C; R¹, K, L and R² form a fused benzene ring; n=0; s=1; t=2; R⁴ andR⁵═H; R³ absent; single bonds from L to X and from X to Y):

can be prepared from indene using the procedures disclosed by Chambers,M. S., et al., J. Med. Chem. 1992, 35, 2033-2039, Scheme II. Thiscompound was purchased from WuXi Pharmatech (Shanghai, China).

Spiro[fluorene-9,4′-piperidine] (Formula II wherein K, L, X, Y═C; R¹, K,L and R² form a fused benzene ring; R⁴, X, Y and R⁵ form a fused benzenering; n=0; s=1; t=2; R³ is absent; single bonds from L to X):

can be prepared from fluorene as disclosed in Example 17 (Steps A-B) ofU.S. Pat. No. 5,578,593, which is hereby incorporated by reference.

Ethyl spiro[indene-1,4′-piperidine]-3-carboxylate (Formula II wherein K,L, X, Y═C; R¹, K, L and R² form a fused benzene ring; n=0; s=1; t=2;R⁴═CH₂CO₂Et; R⁵═H; R³ absent; single bond from L to X and double bondfrom X to Y):

can be prepared by deprotection of 1′-tert-butyl 3-ethylspiro[indene-1,4′-piperidine]-1′,3′-dicarboxylate which can be preparedfrom tert-butyl3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate asdisclosed in Example 1 (Steps A-C) of U.S. Pat. No. 5,965,565, which ishereby incorporated by reference. This compound was purchased from WuXiPharmatech (Shanghai, China).

(±)-2,3-Dihydrospiro[indene-1,4′-piperidine]-3-carboxylic acid (FormulaII wherein K, L, X, Y═C; R¹, K, L and R² form a fused benzene ring; n=0;s=1; t=2; R⁴═CO₂H; R⁵═H; R³ absent; single bonds from L to X and from Xto Y):

can be prepared by deprotection of1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylicacid which can be prepared from tert-butyl3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate asdisclosed in Example 1 (Steps A-D) of U.S. Pat. No. 5,965,565, which ishereby incorporated by reference. This compound was purchased from WuXiPharmatech (Shanghai, China).

1,3-Dihydrospiro[indene-2,3′-piperidine] (Formula II wherein K, L, X,Y═C; R², L, X and R⁴ form a fused benzene ring; n=0; s=2; t=1; R¹ andR⁵═H; R³ is absent; single bonds from K to L and from X to Y):

can be prepared from ethyl nipecotate using the procedures disclosed byYang, L., et al., Bioorg. Med. Chem. Lett. 1998, 8, 107-112, Scheme 3.

(±)-2,3-Dihydrospiro[indene-1,3′-pyrrolidine] (Formula II wherein K, L,X, Y═C; R¹, K, L and R⁴ form a fused benzene ring; n=0; s=1; t=1; R⁴ andR⁵═H; R³ is absent; single bonds from L to X and from X to Y):

can be prepared as described in Sarges R., et al., J. Med. Chem. 1988,31, 230-243 (Compound 95, Table XVI).

1,4-dioxa-8-azaspiro[4.6]undecane (Formula II wherein K and Y=0; L andY═C; n=0; s=2; t=2; R² and R⁴═H; M, R¹, R³ and R⁵ are absent; singlebonds from K to L, from L to X and from X to Y):

can be prepared from ethyl hexahydro-4-oxazepine-1-carboxylate asdisclosed in Example A3 (Steps (a) and (b)) of US Published PatentApplication 2003/0139393, which is hereby incorporated by reference.

3H-spiro[isobenzofuran-1,4′-piperidine] (Formula II wherein R¹, K, L andR² form a fused benzene ring; X is C; Y is O; n=0; s=1; t=2; R⁴ is H; M,R³ and R⁵ are absent; single bonds from L to X and from X to Y):

can be prepared as described in Cheng, C. Y., et al., Tetrahedron 1996,52, 10935. 3H-spiro[isobenzofuran-1,4′-piperidine] was purchased from J& W PharmLab LLC (Morrisville, Pa., USA).

2H-spiro[benzofuran-3,4′-piperidine] (Formula II wherein R¹, K, L and R²form a fused benzene ring; X is O; Y is C; n=0; s=1; t=2; R⁵ is H; M, R³and R⁴ are absent; single bonds from L to X and from X to Y):

can be prepared as described in Parham, W. E., et al., J. Org. Chem.1976, 41, 2628.

5-chloro-1-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine] (Formula IIwherein R¹, K, L and R² form a fused chlorine substituted benzene ring;X is N; Y is C; n=0; s=1; t=1; R⁴ is SO₂Me; R⁵ is II; M and R³ andabsent; single bonds from L to X and from X to Y):

can be prepared as disclosed in Example 3 (Steps A-C) of WO 2005/061512A1, which is hereby incorporated by reference.

3,4-Dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine] (Formula E whereinR¹, K, L and R² form a fused benzene ring; K, L, M, X and Y art C; n=1;s 1; t=1; R³, R⁴ and R⁵ are H; single bonds from L to M, from M to X andfrom X to Y):

can be prepared as described in Crooks, P. A., et al., J. Med. Chem.1980, 23, 679.

3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] was purchased fromWuXi Pharmatech (Shanhai, China):

Tert-butyl 1H-Spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate waspurchased from WuXi Pharmatech (Shanhai, China):

-   6-Methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]:

was prepared as disclosed in Procedure A in U.S. Pat. No. 7,109,207(Column 25, Line 5), which is hereby incorporated by reference.

Spiro[chroman-2,4′-piperidine] (Formula II wherein R², L, M and R³ forma fused benzene ring; K=0; M, L, X and Y are C; n=1; s=1; t=2; R⁴ and R⁵are H; single bonds from L to M, from M to X and from X to Y):

can be prepared as disclosed in Example 12 (Step A) of U.S. Pat. No.5,536,716, which is hereby incorporated by reference.

Spiro[chroman-2,4′-piperidine]-4-carboxylic acid (Formula II wherein R²,L, M and R³ form a fused benzene ring; K=0; L, M, X and Y are C; n=1;s=1; t=2; R⁴ is CO₂H; R⁵ is H; single bonds from L to M, from M to X andfrom X to Y):

was prepared by deprotection of1′-(tert-butoxycarbonyl)spiro[chroman-2,4′-piperidine]-4-carboxylicacid, which was purchased from WuXi Pharmatech (Shanghai, China)(catalog number BBA-0011).

2-(spiro[chroman-2,4′-piperidine]-4-yl)acetic acid (Formula II whereinR², L, M and R³ form a fused benzene ring; K=0; L, M, X and Y are C;n=1; s=1; t=2; R⁴ is CH₂CO₂H; R⁵ is H; single bonds from L to M, from Mto X and from X to Y):

was prepared by deprotection of2-(1′-(tert-butoxycarbonyl)spiro[chroman-2,4′-piperidine]-4-yl)aceticacid, which was purchased from WuXi Pharmatech (Shanghai, China)(catalog number BBA-0012).

In the first process of the invention, chloroformates of formula III areprepared by reaction of alcohols of formula IV with phosgene ortriphosgene in an inert solvent such as toluene, CH₂Cl₂ or THF in thepresence of a base such as pyridine at −20° C. to 80° C., preferably 0°C. to 25° C. for between 0.5 h and 24 h.

In the second process of the invention, a compound of Formula I or I*wherein Q ═NH is prepared by reaction of an amine of formula II with anisocyanate of formula V in the presence of an organic or inorganic base,for example N,N-diisopropylethylamine or K₂CO₃, in an inert solvent suchas CH₂Cl₂, MeCN or THF at −20° C. to 80° C., preferably 0° C. to 25° C.for between 0.5 h and 24 h.

Isocyanates of formula V are prepared by reaction of amines of formulaVI with phosgene or triphosgene in, for example, a mixture of CH₂Cl₂ andsatd aq NaHCO₃ at −10° C. to 80° C., preferably 0° C. to 25° C. forbetween 0.5 h and 24 h.

In the third process of the invention, a compound of Formula I or I*wherein Q=NR⁶ is prepared by reaction of an amine of formula II with acompound of Formula VII wherein LG is a leaving group such as halide,aryloxide or azole, for example chloride, p-nitrophenoxide orimidazolide, in an inert solvent such as CH₂Cl₂, MeCN or THF at 0° C. to120° C., preferably 25° C. to 75° C. for between 0.5 h and 24 h.

Intermediates of formula VII wherein LG=aryloxide are prepared byreaction of amines of formula VIII with an aryl chloroformate IX in, forexample, MeCN or CH₂Cl₂ in the presence of DIEA or powdered NaHCO₃ at−10° C. to 50° C., preferably 0° C. to 25° C. for between 0.5 h and 24h.

Intermediates of formula VII wherein LG=Cl and R⁶ is not H are preparedby treatment of amines of formula VIII with phosgene or triphosgene at−70° C. to 25° C. in an inert solvent such as CH₂Cl₂, THF or MeCN forbetween 30 min and 24 h.

Intermediates of formula VII wherein LG=1-imidazolyl and are prepared bytreatment of amines of formula VIII with carbonyl diimidazole in aninert solvent such as CH₂Cl₂, THF, toluene or MeCN at −40° C. to 60° C.,preferably at −10° C. to 30° C., for 15 min to 12 h.

In the fourth process of the invention, a compound of Formula I or I*wherein Q=NR⁶ is prepared by reaction of an intermediate of formula IX,wherein LG is a leaving group such as such as halide, aryloxide orazole, for example chloride, p-nitrophenoxide or imidazolide, with anamine of formula VIII in an inert solvent such as CH₂Cl₂, MeCN or THF at0° C. to 120° C., preferably 25° C. to 75° C. for between 0.5 h and 24h.

Intermediates of Formula IX are prepared from intermediates of FormulaII using procedures and conditions analogous to those described abovefor the preparation of intermediates of Formula VII from amines ofFormula VIII.

In the fifth process of the invention, a compound of Formula I or I*wherein Q=O is prepared by reaction of an intermediate of formula IX,wherein LG is a leaving group such as such as halide, aryloxide orazole, for example chloride, p-nitrophenoxide or imidazolide, with analcohol of formula IV an inert solvent such as CH₂Cl₂, MeCN or THF at25° C. to 150° C., preferably 25° C. to 100° C. for between 0.5 h and 24h.

In the sixth process of the invention, a compound of Formula I or I* isprepared by derivatizing compound of Formula I or I* that has a reactivesite such as an amine or carboxylic acid. Examples of the sixth processinclude the following:

a) reaction of a compound of Formula I or I* wherein X═N and R⁴═H withan acid chloride of Formula X in an inert solvent such as CH₂Cl₂,toluene or THF in the presence of a soluble organic base such aspyridine or triethylamine or in the presence of an aqueous base(Schotten-Baumann conditions) at −40° C. to 50° C., preferably from −20°C. to 5° C. for between 0.5 hand 30 h, to give a compound of Formula Ior I*wherein X═N and R⁴═COR⁶:

b) reaction of a compound of Formula I or I* wherein X═N and R⁴═H with asulfonyl chloride of Formula XI in an inert solvent such as CH₂Cl₂ orTHF in the presence of an amine base such as pyridine or DMAP at 0° C.to 125° C., preferably 20° C. to 100° C., to give a compound of formulaI or I* wherein X═N and R⁴═SO₂R⁶:

c) reaction of a compound of Formula I or I* wherein X═N and R⁴═H with achloroformate of Formula XII in the presence of an organic or inorganicbase, for example N,N-diisopropylethylamine or K₂CO₃, in an inertsolvent such as CH₂Cl₂, MeCN or THF at −20° C. to 80° C., preferably 0°C. to 25° C. for between 0.5 h and 24 h to give a compound of formula Ior I* wherein X═N and R⁴═CO₂R⁶:

d) reaction of a compound of Formula I or I* wherein X═C and R⁴=ACO₂Hwith an alcohol of Formula XIII in the presence of an acid such asanhydrous HCl gas at 0° C. to 25° C. for between 0.5 h and 24 h, to givea compounds of formula I or I* wherein X═C and R⁴=ACO₂R⁶:

e) reaction of a compound of Formula I or I* wherein X═CH and R⁴=ACO₂Hwith an amine of Formula XIV in the presence of a peptide bond formingreagent such as EDC/HOBt, PyBOP or HATU in CH₂Cl₂ or DMF at 0° C. to 40°C. for between 0.5 h and 24 h to give a compound of formula I or I*wherein X═CH and R⁴=ACON(R⁶)₂:

f) reaction of a compound of formula I or I* wherein X═C and R⁴=ACONH₂with a dehydrating agent such as trifluoroacetic anhydride or POCl₃ inthe presence of pyridine or 2,6-lutidine in CH₂Cl₂ or THF at −70° C. to25° C. for 0.5 h give a compound of formula I or I* wherein X═C andR⁴=AC≡N:

g) reaction of a compound of Formula I or I* wherein X═C and R⁴=AC≡Nwith azidotrimethylsilane in toluene or xylenes in the presence of(Bu₃Sn)₂O at 80° C. to 175° C. for between 0.5 h and 24 h to give acompound of formula I or I* wherein X═C and R⁴=A-(5-tetrazolyl):

h) reaction of a compound of Formula I or I* wherein X═C and R⁴=ACO₂Hwith a sulfonamide of formula XV in the presence of carbonyl diimidazolein an inert solvent such as CH₂Cl₂ or THF at 0° C. to 50° C. to give acompound of Formula I or I* wherein X═C and R⁴=AC(O)NR⁶SO₂R⁶:

i) reaction of a compound of Formula I or I* wherein R⁷ is a bi- ortricycloalkyl group bearing a CO₂Me substituent with an alkali metalhydroxide in a mixture of water and a lower alkanol or THF at 0° C. to50° C. between 3 h and 24 h to give a compound of Formula I or I*wherein R⁷ is a bi- or tricycloalkyl group bearing a CO₂H substituent:

j) reaction of a compound of Formula I or I* wherein R⁷ is a bi- ortricycloalkyl group bearing a CO₂Me substituent with a nucleophilicspecies such as iodide or a thiol anion to give a compound of Formula Ior I* wherein R⁷ is a bi- or tricycloalkyl group bearing a CO₂Hsubstituent:

k) a two step reaction of a compound of Formula I or I* wherein R⁷ is abi- or tricycloalkyl group bearing a CO₂H substituent with thionylchloride or ox CH₂Cl₂ at −20° C. to 80° C. for between 0.5 h and 24 h toconvert the CO₂H substituent to an acid chloride substituent followed bytreatment with at least one equivalent of ammonia in an inert solventsuch as CH₂Cl₂ or THF, optionally in the presence of a base such astriethylamime or pyridine, at −20° C. to 40° C. to give a compound ofFormula I or I* wherein R⁷ is a bi- or tricycloalkyl group bearing aCONH₂ substituent:

l) reaction of a compound of Formula I or I* wherein R⁷ is a bi- ortricycloalkyl group bearing a CO₂Me substituent with an alkaliborohydride in THF at −20° C. to 50° C. for between 1 h and 24 h to givea compound of Formula I or I* wherein R⁷ is a bi- or tricycloalkyl groupbearing a CH₂OH substituent:

Purification Methods

Unless otherwise specified, prep HPLC refers to preparative reversephase HPLC on a C-18 column eluted with a water/acetonitrile gradientcontaining 0.01% TFA run on a Gilson 215 system.

Analytical Methods

LC-MS Method 1

Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, B: 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 2.0 10 90 2.4 10 90 2.5 90 10 3.0 90 10LC-MS Method 2Column: YMC ODS-AQ, S-5 mm, 12 nm, 50×2.0 mm ID; Column temperature 40°C.; Mobil phase: A: H₂O+0.1% TFA, B: MeCN+0.05% TFA; Flow rate: 0.8mL/min; Gradient:

Time (min) A % B % 0.00 100 0 0.4 100 0 2.00 40 60 2.50 40 60 2.51 100 04.00 100 0LC-MS (16 min) Method 3Column: Chromolith SpeedRod, RP-18e, 50×4.6 mm; Mobil phase: A: 0.01%TFA/water, 0.01% TFA/CH₃CN; Flow rate: 1 mL/min; Gradient:

Time (min) A % B % 0.0 90 10 14.0 10 90 15.0 10 90 15.1 90 10 16.0 90 10Method 4 (10-80)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0   90 10 2.2 20 80 2.5 20 80 Flow Rate 1 mL/min Wavelength UV 220 nmOven Temp 50° C. MS ESI ionizationMethod 5 (30-90)

Column YMC-PACK ODS-AQ, 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA(1.5 mL)) Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B% 0   70 30 2.2 10 90 2.5 10 90 Flow Rate 1 mL/min Wavelength UV220 OvenTemp 50° C. MS ESI ionizationMethod 6 (50-100)

Column Sepax HP 50 × 2.0 mm 5 μm Mobile A: water (4 L) + TFA (1.5 mL))Phase B: acetonitrile (4 L) + TFA (0.75 mL)) TIME (min) A % B % 0   50  50 2.2  0 100 2.48 0 100 Flow Rate 1 ml/min Wavelength UV220 Oven Temp50° C. MS ESI ionization

Synthetic Preparations Preparation 1 2-Adamantyl Isocyanate

A vigorously stirred mixture of 2-aminoadamantane hydrochloride (5.01 g,26.7 mmol), CH₂Cl₂ (50 mL) and satd aq NaHCO₃ (50 mL) was cooled in anice bath. After 15 min, solid triphosgene (2.64 g, 8.9 mmol) was added.The mixture was stirred in the ice bath for 30 min and the layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (100 mL). Thecombined organic layers were washed with brine (50 mL), dried over MgSO₄and concentrated under reduced pressure to afford the title compound(3.55 g, 75%) as a white solid.

Preparation 2 2-Adamantyl Chloroformate

The title compound was prepared from 2-adamantanol as disclosed inExample 74 (Step (a)) of U.S. Pat. No. 5,270,302, which is herebyincorporated by reference.

Preparation 3 1-Methoxycarbonyl-4-adamantyl chloroformate

Step 1

A stirred solution of 4-oxoadamantane-1-carboxylic acid (4.42 g, 22.8mmol) in MeOH (100 mL) was cooled in an ice bath and NaBH₄ tablets (4×1g, 106 mmol) were added at 15 min intervals. The ice bath was allowed tomelt and the mixture was stirred overnight at rt and concentrated underreduced pressure. The residue was diluted with 5% aq HCl (100 mL) andextracted with ether (2×125 mL). The combined ether extracts were driedover MgSO₄ and concentrated to give 4-hydroxyadamantane-1-carboxylicacid (4.47 g, quant) as an off-white solid which was used directly.

Step 2

To a stirred solution of 4-hydroxyadamantane-1-carboxylic acid (4.47 g,22.8 mmol) in MeOH (75 mL) was added 4 M HCl in dioxane (25 mL, 100mmol). The mixture was stirred at rt for 2 d and concentrated. Theresidue was purified by chromatography on a 40-g silica cartridge elutedwith a 0-80% EtOAc in hexanes gradient to afford methyl4-hydroxyadamantane-1-carboxylate (4.04 g, 84%) as a clear, colorlessoil.

Step 3

A stirred solution of methyl 4-hydroxyadamantane-1-carboxylate (1.01 g,4.8 mmol) and pyridine (0.38 mL, 4.8 mmol) in CH₂Cl₂ (25 mL) was cooledin an ice bath and a solution of triphosgene (0.48 g, 1.6 mmol) inCH₂Cl₂ (10 mL) was added dropwise over 15 min. The mixture ice bath wasallowed to melt and the mixture was stirred for 3 h. The mixture wasevaporated to dryness and the residue was triturated with EtOAc (100mL). The filtrate was concentrated to afford1-methoxycarbonyl-4-adamantyl chloroformate (1.19 g, 91%) as an oilwhich solidified on standing.

Preparation 4 Spiro[indene-2,3′-piperidin]-1(3H)-one

Step 1

To a solution of ethyl piperidine-3-carboxylate (67.74 g, 266 mmol) indry CH₂Cl₂ (300 mL) was added TEA (40.34 g, 399 mmol) at 0° C. Benzoylchloride (41.13 g, 293 mmol) was added slowly to control any rise inreaction temperature. After addition was complete, the mixture wasstirred at rt overnight. The mixture was washed with 1N aq HCl andbrine. The organic layer was dried with anhydrous Na₂SO₄ andconcentrated to leave a residue, which was purified by silica gel columnchromatography (petroleum/ethyl acetate 5:1 to 3:1) to afford ethyl1-benzoylpiperidine-3-carboxylate (62.63 g, 90%). ¹H NMR (CD₃OD, 400MH_(z)): δ=1.41 (t, 3H), 1.52 (m, 2H), 1.85 (m, 2H), 2.36 (s, 1H), 3.29(m, 2H), 3.81 (m, 4H), 7.22 (m, 3H), 7.42 (m, 2H).

Step 2

To a solution of ethyl 1-benzoylpiperidine-3-carboxylate (9.22 g, 35mmol) in dry THF (55 mL) at −78° C. was added dropwise LDA (39 mmol, 1.1eq) in 45 mL of dry THF. After addition, the reaction was stirred for 1h. Then benzyl bromide (6.54 g, 39 mmol, 1.1 eq) was added dropwiseunder the an atmosphere of N2. The reaction was stirred for another 3 h.The solution was added dropwise 5% HCl at 0° C. and concentrated. Theaqueous residue was extracted with CH₂Cl₂. The combined organic extractswere dried over anhydrous Na₂SO₄ and evaporated to afford ethyl1-benzoyl-3-benzylpiperidine-3-carboxylate (11.16 g, 91%). ¹H NMR(CD₃OD, 400 MH_(z)): δ=1.30 (t, 3H), 1.50˜1.55 (m, H), 2.75 (m, 2H),3.65 (m, 4H), 4.09 (m, 2H), 7.08 (m, 2H), 7.22 (m, 3H), 7.48 (m, 5H).

Step 3.

Ethyl 1-benzoyl-3-benzylpiperidine-3-carboxylate (6.308 g; 18 mmol) washydrolyzed with 1 N aq NaOH (220 mL) in ethanol (110 mL) for 20 h at rt.The ethanol was removed by rotary evaporation and the aqueous layer wasextracted once with CH₂Cl₂. The pH of the aqueous layer was adjusted topH=3-4 with 1 N aq HCl and extracted with CH₂Cl₂ (3×). The organic phasewas dried over anhydrous Na₂SO₄, filtered and evaporated to give1-benzoyl-3-benzylpiperidine-3-carboxylic acid (3.24 g, 55.7%). ¹H NMR(CD₃OD, 400 MH_(Z)): δ=1.12 (m, 3H), 1.50˜1.72 (m, 4H), 2.18 (m, 1H),2.75 (d, 1H), 3.05 (m, 1H), 3.16 (m, 1H), 4.08 (m, 2H), 7.08 (m, 2H),7.22 (m, 3H), 7.48 (m, 5H).

Step 4

A mixture of 1-benzoyl-3-benzyl-piperidine-3-carboxylic acid (6.71 g,20.7 mmol) and thionyl chloride (2.70 g, 22.77 mmol) in dry CH₂Cl₂ (25mL) was heated to reflux for 30 min. The resulting solution wasconcentrated in vacuum to give alight brown oil. A solution of this oilin dry CH₂Cl₂ (25 mL) was added dropwise to a mixture of AlCl₃ (3.59 g,26.91 mmol) in CH₂Cl₂ (10 mL) at 0° C. The mixture was stirred for 15min at 0° C. and then heated to reflux for 45 min. The mixture wascooled and poured onto crushed ice and 12 N aq HCl. The organic layerwas separated, washed with 3 N aq HCl, saturated Na₂CO₃, water andbrine. Finally the organic layer was concentrated to give a residue,which was purified by silica gel column chromatography (petroleum/ethylacetate 5:1 to 1:1) to afford1′-benzoylspiro[indene-2,3′-piperidin]-1(3H)-one (3.24 g, 51%). ¹H NMR(CD₃OD, 400 MHz): δ=1.61 (m, 4H), 2.68 (m, 2H), 3.46 (m, 4H), 7.34 (m,8H), 7.64 (m, 2H).

Step 5

1′-benzoylspiro[indene-2,3′-piperidin]-1(3H)-one (2.476 g, 8.11 mmol)was dissolved in methanol (40 mL). 1 N aq HCl (80 mL) was added dropwiseand the mixture was refluxed overnight. The methanol was removed invacuo. The pH of the solution was adjusted to 8 using saturated Na₂CO₃,and the solution was extracted with CH₂Cl₂. The combined organicextracts were dried over anhydrous Na₂SO₄ and then concentrated toafford a residue, which was purified by silica gel column chromatographyto afford spiro[indene-2,3′-piperidin]-1(3H)-one (460 mg, 28%). ¹H NMR(CD₃OD, 400 MH_(z)): δ=1.63 (m, 2H), 1.82 (m, 1H), 1.87-2.00 (m, 1H),2.70 (d, 1H), 2.82 (m, 1H), 3.00 (m, 3H), 3.20 (d, 1H), 7.32 (m, 1H),7.45 (m, 1H), 7.57 (m, 1H), 7.79 (m, 1H).

Preparation 5 Ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate

Step 1

To a solution of tert-butyl 7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3,dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (500 mg, 1.11 mmol)was added LiHMDS (2.4 mL, 1 M, 2.4 mmol) at −10° C. under nitrogen. Themixture was stirred for 1 h and CH₃I (472 mg, 3.3 mmol) was added. Afteraddition, the mixture was stirred overnight. The solution was quenchedwith satd aq NH₄Cl, the organic phase was separated, dried andconcentrated to give crude product which was purified by preparative TLCto give tert-butyl7-bromo-3-(1-ethoxy-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(60 mg, 11%). ¹H NMR: (400 MHz, CDCl₃): δ=0.96 (d, 3H), 1.23 (t, 3H),1.28 (m, 1H), 1.41 (s, 9H), 1.62 (m, 1H), 2.32 (m, 2H), 2.73 (m, 3H),3.08 (m, 1H), 3.61 (m, 1H), 4.07 (d, 2H), 4.12 (q, 2H), 6.94 (m, 2H),7.28 (m, 1H).

Step 2

Tert-butyl7-bromo-3-(1-ethoxy-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(300 mg, 0.645 mol) was dissolved in 20% TFA at 0° C. The reactionmixture was stirred for 1′ h at rt. The solvent was removed underreduced pressure to give ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (235mg, 100%). ¹H NMR: (400 MHz, CDCl₃): δ=0.98 (d, 3H), 1.23 (t, 3H),1.61-1.73 (m, 4H), 2.42 (m, 1H), 2.73 (m, 1H), 3.01 (m, 1H), 3.23 (m,3H), 3.48 (m, 3H), 3.68 (d, 1H), 4.21 (q, 2H), 7.03 (m, 2H), 7.38 (d,1H).

Preparation 6 Ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate

Step 1

To a solution of tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(500 mg, 1.11 mmol) was added LiHMDS (2.4 mL, 1 M, 2.4 mmol) followed byHMPA at −10° C. under N₂. The mixture was stirred for 1 h and CH₃I (142mg, 8.8 mmol) was added to the solution. After addition, the mixture wasstirred overnight. The solution was quenched by saturated NH₄Cl, theorganic phase was separated, dried and concentrated to give the crudeproduct which was purified by preparative TLC to give (±)-tert-butyl7-bromo-3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(350 mg, 67%). ¹H NMR: (400 MHz, CDCl₃): δ=1.12 (s, 3H), 1.26 (s, 3H),1.30 (m, 3H), 1.32 (m, 2H), 1.48 (s, 9H), 2.29 (m, 1H), 2.42 (m, 1H),2.93 (m, 3H), 3.16 (m, 1H), 3.78 (m, 1H), 4.16 (m, 2H), 4.25 (m, 2H),6.94 (d, 1H) 7:02 (t, 1H) 7.37 (d, 1H).

Step 2

(±)-Tert-butyl7-bromo-3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(152 mg, 0.317 mol) was dissolved in 20% TFA at 0° C. The mixture wasstirred for 1 h at rt. The solvent was removed under reduced pressure togive (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoatewhich was used without purification (120 mg, 100%).

Preparation 7 4-aminoadamantan-1-ol

To 2-aminoadamantane (10 g, 54 mmol) was added H₂SO₄ (150 mL) and HNO₃(15 ml) at 0° C. and the mixture was stirred overnight. The mixture waspoured onto ice and adjusted to pH=10-11 using 40% aq NaOH under icebath. The mixture was extracted with CH₂Cl₂. The organic layer wasdried, filtered and concentrated to give 4-aminoadamantan-1-ol (3.0 g,14%).

Preparation 8 1-fluoro-4-aminoadamantane

To the solution of 4-aminoadamantan-1-ol (800 mg, 4.79 mmol) inanhydrous toluene (6 mL) was added DAST (780 mg, 5 mmol) at 0° C. Thereaction mixture was refluxed for 8 h. The mixture was cooled to rt andquenched with aq NaHCO₃. The mixture was concentrated and extracted withCH₂Cl₂ (2×). The combined organic extracts were dried, filtered andconcentrated to give 1-fluoro-4-aminoadamantane (700 mg), which was usedwithout purification.

Preparation 9 1,7-dihydroxy-4-aminoadamantane

Step 1

A solution of 2-aminoadamantane (20 g, 108 mmol) in dry pyridine (120mL) was treated with acetic anhydride (12 mL, 128 mmol) and stirredovernight at rt. The mixture was dilute with EtOAc and washed withwater, 1 N aq phosphoric acid and brine. The organic layer was dried,filtered and concentrated to give N-(2-adamantyl)acetamide (12.5 g,60%). ¹H NMR (400 MHz, CDCl₃): δ=1.57 (m, 2H), 1.67 (m, 3H), 1.72 (m,1H), 1.77 (m, 6H), 1.85 (m, 2H), 1.94 (s, 3H), 3.97 (t, 1H), 5.78 (br,1H).

Step 2

To bromine (20 mL, 40 mmol) and aluminum bromide (3.2 g, 20 mmol) wasadded N-(2-adamantyl)acetamide (4 g, 20 mmol) in portions. The reactionmixture was heated to 90° C. and stirred overnight. The mixture wascooled to rt and poured into ice/water. Satd aq sodium bisulfite wasadded slowly followed by dilution with CH₂Cl₂. The organic layer wasseparated, washed with brine, dried, filtered and concentrated. Thecrude product was purified by column chromatography to affordN-(5,7-dibromo-2-adamantyl)acetamide (1.98 g, 28%).

Step 3

To N-(5,7-dibromo-2-adamantyl)acetamide (2 g, 5.73 mmol) and Ag₂SO₄(3.90 g, 12.6 mmol) was slowly added concentrated H₂SO₄ (14 mL). Afteraddition was complete, the reaction mixture was heated to 80° C. for 3h. The mixture was cooled to rt and poured into ice/water. The mixturewas filtered, and the filtrate was neutralized with solid KOH. Themixture was filtered, and the solids were washed with methanol. Thefiltrate was concentrated, and the residue was triturated with methanol.The mixture was filtered, and filtrate was concentrated. The crudeproduct was purified by preparative TLC (DCM/MeOH=5:1) to giveN-(5,7-dihydroxy-2-adamantyl)acetamide (192 mg, 15%). ¹H-NMR (400 MHz,DMSO): δ=1.21 (m, 2H), 1.42 (m, 6H), 1.74 (m, 2H), 1.77 (m, 3H), 1.96(m, 2H), 4.48 (d, 1H), 7.65 (m, 1H).

Step 4

To N-(5,7-dihydroxy-2-adamantyl)acetamide (110 mg, 0.489 mmol) was added4N aq HCl (3 mL) slowly. The reaction mixture was heated to 80° C.overnight. The mixture was cooled to rt and concentrated. The residuewas treated with satd aq NaHCO₃. The water was removed under reducedpressure, and the solid was triturated with methanol. The mixture wasfiltered, and the solids were washed with methanol. The filtrate wasconcentrated give to 6-aminoadamantane-1,3-diol (50 mg, 56%). ¹H-NMR(400 MHz, D₂O): δ=1.45 (m, 2H), 1.63 (m, 6H), 1.73 (m, 4H), 2.12 (m,2H), 3.27 (m, 1H).

Preparation 107-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thione

Step 1

A 100-mL flask was charged with 3-chloro-2-iodobenzoic (2.43 g, 8.64mmol, 0.90 equiv) and thionyl chloride (15 mL). The solution wasvigorously stirred, then 1 drop of DMF added and the mixture heated toreflux for 4 h. During this time the acid dissolved to give a paleyellow solution. The cooled mixture was evaporated and toluene (50 mL)added, then removed in vacuo. The evaporation/dissolution withtoluene/evaporation procedure was repeated twice and the pale yellow3-chloro-2-iodobenzoyl chloride was placed on the vacuum line.

In a separate flask a toluene (30 mL) solution tert-butyl4-oxopiperidine-1-carboxylate (2.45 g, 12.32 mmol, 1.25 equiv),4-methoxybenzylamine (1.352 g, 9.6 mmol, 1.0 equiv) and MgSO₄ (˜20 g)were heated to reflux overnight. The mixture was filtered through a bedof Celite, the cake was washed with toluene (˜30 mL) and the filtratewas evaporated. The amber residue was dissolved in CH₂Cl₂ (100 mL) andTEA (1.94 g, 2.7 mL, 19.2 mmol, 2.0 equiv) and DMAP (117 mg, 0.96 mmol,0.1 equiv) were added. The 3-chloro-2-iodobenzoyl chloride preparedabove was dissolved in CH₂Cl₂ (10 mL) and the resultant solution addedto the enamine solution over a ˜10 min period, then stirred overnight.The reaction was quenched by addition of 1.0 M aq HCl (100 mL) and themixture was transferred to a separatory funnel. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and evaporated. Theresidue was purified by flash chromatography on silica gel (120 g)eluting with 19-71% EtOAc in hexanes tert-butyl4-(3-chloro-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate(˜3.19 g, ˜5.47 mmol, ˜63% yield), contaminated with ˜5%3-chloro-2-iodo-N-(4-methoxylbenzyl)benzamide, was isolated as a paleyellow foam.

Step 2

Tert-butyl4-(3-chloro-2-iodo-N-(4-methoxybenzyl)benzamido)-5,6-dihydropyridine-1(2H)-carboxylate(˜3.19 g, ˜5.47 mmol) was dissolved in DMF (30 mL) in a three neck flaskfitted with a condenser and the mixture was purged with N₂ gas for ˜1 h.Against a counterflow of N₂ the flask was quickly opened and Pd(OAc)₂(61 mg, 0.274 mmol, 5 mol %), rac-BINAP (340 mg, 0.548 mmol, 10 mol %),DIEA (1.56 g, 2.1 mL, 11.0 mmol, 2.0 equiv) and Et₄NCl (980 mg, 5.47mmol, 1.0 equiv) were added. The mixture was heated to reflux for 17 h.After this time, the iodide had been consumed and the mixture was cooledto rt and evaporated. The residue was taken up in EtOAc/H₂O and thelayers were separated. The organic layer was washed with brine, driedover Na₂SO₄, and evaporated. The crude product was purified by flashchromatography on silica gel, eluting with 20-80% EtOAc in hexanestert-butyl7-chloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylatewas isolated as a pale yellow foam (1.72 g, 69%).

Step 3

Tert-butyl7-chloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate(1.69 g, 3.71 mmol, 1.0 equiv) and PtO₂ (100 mg, 0.440 mmol, 12 mol %)were added to a solution of 1:1 4.0 M HCl:MeCN (200 mL). The mixture wastransferred to a Parr hydrogenation vessel and hydrogenated at 55 psifor 3 d. After this time the vessel was vented and the pale yellowsolution filtered through a bed of Celite. The mixture was evaporatedand the residue was dissolved in 1:1 MeCN:10% aq K₂CO₃ (200 mL); Boc₂O(1.21 g, 5.56 mmol, 1.5 equiv) was added and the mixture was stirred for17 h. After this time the solution was evaporated and the residue wasdiluted with EtOAc. The organic layer was washed with 1.0 M aq HCl andbrine, dried over Na₂SO₄, and evaporated. The reduced product waspurified by flash chromatography on silica gel, eluting with 20-80%EtOAc in hexanes. Tert-butyl7-chloro-2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylatewas isolated as a pale yellow foam (0.702 g, 1.54 mmol, 42%).

Step 4

Tert-butyl7-chloro-2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate(50 mg, 0.110 mmol, 1.0 equiv) and Lawesson's reagent (220 mg, 0.55mmol, 5.0 equiv) were added to toluene (10 mL) and the mixture heated to80° C. for 17 h. The mixture was cooled to rt and filtered through aplug of Celite. The filtrate was evaporated and the residue purified byflash chromatography on silica (4 g, eluting with 19-71% EtOAc inhexanes tert-butyl7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate(52 mg, 0.11 mmol, >99% yield) was isolated as a pale yellow solid.

Step 5

Tert-butyl7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate(52 mg, 0.11 mmol) was dissolved in neat TFA (−2 mL): After 0.5 h LC-MSshowed removal of the boc group. The mixture was evaporated to affordcrude7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thioneas its TFA salt which was used without purification.

7-chloro-2-methylspiro[isoindoline-1,4′-piperidine]-3-thione wasprepared following procedures analogous to those described inPreparation 10 using methylamine in Step 1 in place of4-methoxybenzylamine.

2-methylspiro[isoindoline-1,4′-piperidine]-3-thione was preparedfollowing procedures analogous to those described in Preparation 10using 2-iodobenzoyl chloride in place of 3-chloro-2-iodobenzoyl chlorideand methylamine in place of 4-methoxybenzylamine in Step 1.

Preparation 11 Spiro[isoindoline-1,4′-piperidine]-3-thione

Step 1

Tert-butyl2-(4-methoxybenzyl)-3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate(50 mg, 0.12 mmol, 1.0 equiv) and TFA (7 mL) were heated to 75° C. for19 h. After this time LC-MS showed removal of the Boc- andp-methoxybenzyl groups. The mixture was concentrated to leave crudespiro[isoindoline-1,4′-piperidin]-3-one which was used directly.

Step 2

Crude spiro[isoindoline-1,4′-piperidin]-3-one was dissolved in 1:1MeCN:10% aq K₂CO₃ (20 mL) and Boc₂O (50 mg, 0.23 mmol, 2.0 equiv) added.The mixture stirred for 3 h. The solution was evaporated and the mixturewas diluted with EtOAc. The organic layer was washed with 1.0 M aq HCland brine, dried over Na₂SO₄, and evaporated. The residue was purifiedby flash chromatography on silica, eluting with 20-80% EtOAc in hexanesto afford tert-butyl3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate.

Steps 3 and 4

Tert-butyl 3-oxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate andLawesson's reagent (˜150 mg, ˜0.37 mmol, 3 equiv) were dissolved intoluene and heated to reflux overnight. The mixture was evaporated,taken up in CH₂Cl₂, (˜10 mL) and filtered through a plug of Celite. Thefiltrate was treated with TFA (˜2 mL). The mixture was stirred for 3 hat rt and evaporated to afford crudespiro[isoindoline-1,4′-piperidine]-3-thione as its TFA salt.

Preparation 12 Tert-butyl7-chloro-3-hydroxy-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate

Step 1

2.5 M n-BuLi in hexanes (9.2 mL, 23 mmol) was added To a stirredsolution of 2,2,6,6-tetramethylpiperidine (3.2 g, 23 mmol) in anhydrousTHF (30 mL) at −20° C. under N₂. The mixture was stirred for 1 h. at−20° C. and then cooled to −78° C. 3-Chlorobenzoic acid (1.8 g, 11.5mmol) in anhydrous THF (20 mL) was slowly added dropwise and the mixturewas stirred for 1 h at −78° C. The mixture was treated with tert-butyl4-oxopiperidine-1-carboxylate (2.29 g, 11.5 mmol) and the resultingsolution was warmed to rt and stirred overnight. The mixture wasquenched with water and extracted with EtOAc (3×30 mL). The organiclayers were combined, washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was Purified bychromatography to give tert-butyl7-chloro-3-oxo-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(500 mg, 13%). ¹H NMR (CD₃OD): δ=1.45 (s, 9H), 2.60 (m, 2H), 3.20 (b,2H), 4.20 (b, 2H), 7.48 (m, 1H), 7.55 (m, 1H), 7.75 (m, 1H).

Step 2.

DIBAL (1 M, 2.4 mL, 2.4 mmol) was added to a solution oftert-butyl-7-chloro-3-oxo-3H-Spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(200 ing, 0.6 mmol) in CH₂Cl₂ (5 mL) at −78° C. The mixture was stirredat −70° C. for 30 min. After the starting material was consumed, thereaction was quenched with methanol, followed by satd aq potassiumsodium tartarate tetrahydrate, and stirred for 1 h. The mixture wasfiltered and the filtrate was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the crude product, which was purified bypreparative TLC to provide tert-butyl7-chloro-3-hydroxy-3,1-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(160 mg, 78%). ¹H NMR (CDCl₃): δ=1.44 (s, 9H), 1.51 (m, 2H), 1.64 (m,H), 2.30-2.64 (m, 2H), 3.18 (m, 2H), 4.00-4.18 (m, 2H), 6.35-6.56 (m,1H), 7.06 (m, 1H), 7.27 (m, 2H).

The following examples are intended to illustrate various embodiments ofthe invention and are not intended in any way to restrict the scopethereof.

EXAMPLES Example 1 Tert-butyl1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate

A stirred solution of 2-adamantanamine hydrochloride (81.1 mg, 0.432mmol) and DIEA (557 mg, 4.32 mmol) in anhydrous CH₂Cl₂ (5 mL) was cooledto 0° C. and CDI (84 mg, 0.52 mmol) was added. The mixture was stirredfor 1 h at 0° C. and tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate (140 mg, 0.43 mmol) inanhydrous CH₂Cl₂ (5 mL) was added. The reaction mixture was allowed towarm to rt and stirred overnight. The reaction mixture was concentratedand the residue was purified by preparative TLC to provide tert-butyl1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylateas a white solid (50 mg, 25%). ¹H NMR (CD₃OD, 400 MH_(z)): δ=1.58˜2.01(m, 28H), 2.92 (t, 2H), 3.91 (d, 2H), 4.09 (d, 2H), 5.85 (d, 1H),6.95˜7.85 (m, 4H); MS: 466 (M⁺+1); LC-MS (4 min) t_(R)=2.70 min,m/z=466.

Example 2 N-(2-Adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

A 10-mL round-bottomed flask was charged with tert-butyl1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate(50 mg, 0.107 mmol) and 20% trifluoroacetic acid in CH₂Cl₂ (2 mL). Themixture was stirred for 1 h at 0° C. The solution was concentrated undervacuum and the crude product was purified by preparative HPLC to provideN-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (10 mg,25%). ¹H NMR (CD₃OD, 400 MH_(z)): δ=1.60˜2.00 (m, 18H), 3.00 (t, 2H),3.86 (d, 3H), 4.08 (d, 2H), 7.40˜7.50 (m, 4H); LC-MS (4 min) t_(R)=1.93min, m/z=366 (M⁺+1).

Example 3(±)-2-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

Step 1

2-(1′-(Tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (200 mg, 0.58 mmol) was added to a solution of 20% trifluoroaceticacid in anhydrous CH₂Cl₂ (3 mL) at 0° C. The reaction solution wasstirred at rt for 2 h until the starting material had been consumed. Thesolution was concentrated to give crude2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (160 mg)which was used in the next step without further purification.

Step 2

To a solution of 2-aminoadamantane hydrochloride (120 mg, 0.64 mmol) andCDI (141 mg, 0.87 mmol) in anhydrous CH₂Cl₂ (4 mL) at 0° C. was addedDIEA (374 mg, 2.90 mmol). The mixture was stirred at 0° C. for 1 h. Asolution of compound2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (142 mg,0.58 mmol) was added dropwise slowly. The mixture was stirred at rtovernight and concentrated to give the crude product. A portion of thecrude product was purified by preparative HPLC to give2-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (60 mg, 36%). ¹H NMR: (400 MHz, CDCl₃): δ=1.56-1.73 (m, 6H),1.74-1.90 (m, 10H), 1.95 (m, 2H), 2.10 (m, 1H), 2.45 (m, 1H), 2.60 (m,1H), 3.01 (m, 3H), 3.65 (m, 1H), 3.87-3.99 (m, 3H), 7.15-7.26 (m, 4H);LC-MS (4 min) t_(R)=2.70 min, m/z=423 (M⁺+1).

Example 4 (±)-Methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

To a solution of2-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (150 mg, 0.355 mmol) in methanol (2 mL) at 0° C. was added thionylchloride (54 mg, 0.46 mmol). The mixture was stirred at rt overnight andconcentrated. The residue was purified by preparative TLC to give methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(62.8 mg, 41%). ¹H NMR (400 MHz, CDCl₃): δ=1.52-1.73 (m, 6H), 1.73-1:81(m, 3H), 1.82-1.90 (m, 7H), 1.95 (m, 2H), 2.10 (m, 1H), 2.45 (m, 1H),2.60 (m, 1H), 3.01 (m, 3H), 3.65 (m, 1H), 3.74 (s, 1H), 3.86 (d, 1H),3.99 (m, 2H), 4.87 (s, 1H), 7.13-7.26 (m, 4H); LC-MS (4 min) t_(R)=2.38min, m/z=437(M⁺+1).

Example 5 Separation of the Enantiomers of Methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

Methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatewas submitted to preparative HPLC on a 10 mm×250 mm Chiral TechnologiesChiralcel OD-H column eluted with 4 mL min⁻¹ of 10% isopropanol inhexanes containing 0.025% diethylamine for 30 min. The isomer thateluted first (t_(R)=23 min) was designated Example 5A. ¹H NMR (CDCl₃)δ=2.05 (m, 1H), 2.43 (m, 1H), 2.60 (m, 1H), 2.92 (m, 1H), 3.05 (m, 2H),3.65 (m, 1H), 3.74 (s, 3H), 3.90 (d, 1H), 4.00 (m, 1H), 4.82 (d, 1H).

The isomer that eluted second (t_(R)=26.5 min) was designated Example5B. ¹H NMR (CDCl₃) δ=2.05 (m, 1H), 2.43 (m, 1H), 2.60 (m, 1H), 2.92 (m,1H), 3.05 (m, 2H), 3.65 (m, 1H), 3.74 (s, 3H), 3.90 (d, 1H), 4.00 (m,1H), 4.82 (d, 1H).

Example 62-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

To a stirred solution of methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer A (2.0 mg, 5 μmol) in water (0.25 mL), THF (0.25 mL) and methanol(0.5 mL) was added LiOH.H₂O (10 mg, 0.23 mmol). The mixture was stirredovernight at rt. The mixture was diluted with 5% aq HCl (10 mL) andextracted with EtOAc (2×40 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated to leave crude2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer A (3 mg, quant) as an oil. ¹H NMR (CDCl₃) δ=2.49 (m, 1H),2.63 (m, 1H), 3.00 (m, 1H), 3.1 (1H), 3.65 (1H), 3.92 (1H), 4.02 (2H);LC-MS (3 min) t_(R)=1.90 min, m/z=423.

The same procedure was applied to methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer B (2.7 mg, 6 μmol) to afford crude2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer B (2.85 mg, quant) as an oil. ¹H NMR (CDCl₃) δ=2.49 (m, 1H),2.63 (m, 1H), 3.00 (m, 1H), 3.1 (1H), 3.65 (1H), 3.92 (1H), 4.02 (2H);LC-MS (3 min) t_(R)=1.90 min, m/z=423.

Example 71-Acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

To a solutionN-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (50 mg,0.108 mmol) and DIEA (27.86 g, 0.22 mmol) in dry CH₂Cl₂ (2-mL) at 0° C.under nitrogen was added dropwise a solution of acetyl chloride (9.28mg, 0.12 mmol) in CH₂Cl₂ (0.5 mL). The mixture was stirred overnight atrt and evaporated to give a residue, which was purified by preparativeHPLC to provide a white solid1-acetyl-N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide(5.2 mg, 12%). ¹H NMR (400 MHz, CD₃OD): δ=1.61 (s, 1H), 1.653 (d, 2H),1.72 (s, 1H), 1.88 (m, 10H), 2.015 (d, 5H), 2.286 (s, 3H), 3.027 (t,2H), 3.867 (s, 1H), 4.088 (d, 4H), 7.044 (t, 1H), 7.191 (t, 2H), 8.082(d, 1H); LC-MS (4 min) t_(R)=1.59 min, m/z=408(M⁺+1).

Example 8 tert-Butyl94(2-adamantyl)carbamoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

A procedure analogous to that described Example 1 was followed usingtert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate. ¹H NMR (CD₃OD)δ=1.45 (s, 9H), 1.49 (m, 8H), 1.72-2.00 (m, 12H), 3.40 (m, 8H), 3.82 (s,1H), 5.69 (m, 1H); LC-MS (4 min) t_(R)=2.40 min m/z=432.

Example 9 tert-Butyl8-((2-adamantyl)carbamoyl)-2,8-diazaspiro[4.5]decane-2-carboxylate

A procedure analogous to that described Example 1 was followed usingtert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate. ¹H NMR (CD₃OD)δ=1.46 (s, 9H), 1.58 (m, 6H), 1.73-2.06 (m, 14H), 3.20 (s, 2H),3.25-3.54 (m, 6H), 3.82 (s, 1H); LC-MS (4 min) t_(R)=2.92 min, m/z 418.

Example 10 (±)-tert-Butyl7((2-adamantyl)carbamoyl)-2,7-diazaspiro[4.5]decane-2-carboxylate

A procedure analogous to that described Example 1 was followed usingtert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylate. ¹H NMR (CDCl₃)δ=1.44 (s, 9H), 1.50-1.90 (m, 21H), 3.01-3.42 (m, 8H), 3.92 (m, 1H),4.79 (m, 1H); LC-MS (4 min) t_(R)=2.25, m/z=418.

Example 111′-((2-Adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylicacid

A procedure analogous to that described Example 3 was followed using1′-(tert-butoxycarbonyl)spiro[indene-1,4′-piperidine]-3-carboxylic acidin Step 1. ¹H NMR (CD₃OD) δ=1.29 (d, 2H), 1.63 (d, 2H), 1.85 (m, 8H),2.00 (m, 4H), 2.13 (m, 2H), 3.25 (m, 2H), 3.89 (s, 1H), 4.16 (m, 2H),7.26 (m, 2H), 7.38 (m, 1H), 7.85 (s, 1H), 7.92 (m, 1H), LC-MS (4 min)t_(R)=2.48 min, m/z=407.

Example 12(±)-1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylicacid

A procedure analogous to that described Example 3 was followed using1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylicacid in Step 1. ¹H NMR (CD₃OD) δ=1.54 (m, 1H), 1.65 (m, 3H), 1.82 (m,9H), 1.98 (m, 5H), 2.46 (m, 2H), 3.06 (m, 2H), 3.86 (s, 1H), 4.06 (m,3H), 7.21 (m, 3H), 7.39 (m, 1H); LC-MS (4 min) t_(R)=2.44 min, m/z=409.

Example 13(±)-1′-((2-Adamantyl)carbamoyl)spiro[chroman-2,4′-piperidine]-4-carboxylicacid

A procedure analogous to that described Example 3 was followed using1′-(tert-butoxycarbonyl)spiro[chroman-2,4′-piperidine]-4-carboxylic acidin Step 1. ¹H NMR (CD₃OD) δ=1.65 (m, 3H), 1.84 (m, 10H), 1.96 (m, 4H),2.16 (m, 1H), 3.15 (m, 1H), 3.36 (m, 1H), 3.86 (m, 4H), 6.86 (m, 2H),7.15 (m, 1H), 7.23 (m, 1H) LC-MS (4 min) t_(R)=2.44 min, m/z=425.

Example 14(±)-2-(1′-(Cyclohexylcarbamoyl)spiro[chroman-2,4′-piperidine]-4-yl)aceticacid

A procedure analogous to that described Example 3 was followed using 2-0‘-(tert-butoxycarbonyl)spiro[chroman-2,4’-piperidine]-4-yl)acetic acidin Step 1. ¹H NMR (CD₃OD) δ=1.61 (m, 3H), 1.74-1.90 (m, 11H), 1.96 (m,4H), 2.05 (m, 1H), 2.48 (m, 1H), 3.00 (m, 1H), 3.13 (m, 1H), 3.39 (m,2H), 3.74 (m, 1H), 3.84 (m, 2H), 6.84 (m, 2H), 7.08 (m, 1H0, 7.23 (m,1H); LC-MS (4 min) t_(R)=2.52 min, m/z=439.

Example 15 Ethyl1′-((2-adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylate

A procedure analogous to that described Example 4 was followed using1′-((2-adamantyl)carbamoyl)spiro[indene-1,4′-piperidine]-3-carboxylicacid and ethanol. ¹H NMR (CD₃OD) δ=1.40 (m, 5H), 1.63 (m, 2H), 1.84 (m,8H), 1.98 (m, 5H), 2.11 (m, 2H), 3.25 (m, 2H), 3.89 (m, 1H), 4.15 (m,2H), 4.36 (m, 2H0, 7.26 (m, 2H), 7.39 (m, 1H), 7.84 (s, 1H), 7.91 (m,1H); LC-MS (4 min) t_(R)=2.19 min, m/z=435.

Example 16 (±)-Ethyl1′-(cyclohexylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylate

A procedure analogous to that described Example 4 was followed using1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]3-carboxylicacid and ethanol. ¹H NMR (CD₃OD) δ=1.29 (t, 3H), 1.54 (m, 1H), 1.64 (m,2H), 1.86 (m, 9H), 1.96 (m, 5H), 2.43 (m, 2H), 3.04 (m, 2H), 3.86 (s,1H), 4.06 (m, 2H), 4.15 (m, 1H), 4.20 (m, 1H), 7.20 (m, 3H), 7.34 (m,1H); LC-MS (4 min) t_(R)=2.12 min, m/z=437.

Example 17 (±)-Ethyl1′-(cyclohexylcarbamoyl)spiro[chroman-2,4′-piperidine]-4-carboxylate

A procedure analogous to that described Example 4 was followed using1′4(2-adamantyl)carbamoyl)spiro[chroman-2,4′-piperidine]-4-carboxylicacid and ethanol. ¹H NMR (CD₃OD) δ=1.29 (t, 3H), 1.60 (m, 3H), 1.70 (m,1H), 1.83 (m, 9H), 1.96 (m, 4H), 2.11 (m, 2H), 3.14 (m, 1H), 3.48 (m,1H), 3.80 (m, 3H), 3.94 (m, 1H), 4.21 (m, 2H), 6.84 (m, 2H), 7.16 (m,2H); LC-MS (4 min) t_(R)=2.10 min, m/z=453.

Example 18 (±)-Ethyl2-1′-((2-adamantyl)carbamoyl)spiro[chroman-2,4′-piperidine]-4-yl)acetate

A procedure analogous to that described Example 4 was followed using2-0′4(2-adamantyl)carbamoyl)spiro[chroman-2,4′-piperidine]-4-yl)aceticacid and ethanol. ¹H NMR (CD₃OD) δ=1.24 (t, 3H), 1.50 (m, 1H), 1.60 (m,1H), 1.83 (m, 10H), 1.97 (m, 3H), 2.01 (m, 2H), 2.45 (m, 1H), 3.00 (m,1H), 3.12 (m, 1H), 3.47 (m, 2H), 3.73 (m, 1H), 3.84 (m, 2H), 4.15 (m,2H), 6.84 (m, 2H), 7.08 (m, 1H), 7.20 (m, 1H); LC-MS (4 min) t_(R)=2.19min, m/z=467.

Example 19N-(2-Adamantyl)-1-(methylsulfonyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide

A procedure analogous to that described in Example 7 was followed usingmethanesulfonyl chloride. ¹H NMR (CD₃OD) δ=1.63 (m, 2H), 1.75 (m, 2H),1.83 (m, 9H), 1.98 (m, 5H), 2.98 (s, 3H), 3.04 (m, 1H), 3.86 (s, 1H),3.93 (s, 2H), 4.16 (d, 2H), 7.04 (m, 1H), 7.22 (m, 2H), 7.37 (m, 1H);LC-MS (4 min) t_(R)=1.67 min, =444.

Example 20 2-Adamantyl spiro[indoline-3,4′-piperidine]-1′-carboxylate

The title compound was prepared from 1-tert-butyl 1′-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate following a procedureanalogous to Example 2. LC-MS Method 4 t_(R)=2.319 min, m/z=367.2; ¹HNMR (CD₃OD) δ=1.31 (m, 1H), 1.66 (m, 2H), 1.72-1.88 (m, 8H), 1.96 (m,4H), 2.05 (m, 5H), 2.15 (m, 1H), 3.03-3.26 (m, 2H), 3.36 (s, 1H), 3.81(s, 2H), 4.25 (s, 2H), 7.41 (m, 4H).

Example 21 2-Adamantyl5-fluorospiro[indoline-3,4′-piperidine]-1′-carboxylate

The title compound was prepared from 1-tert-butyl 1′-(2-adamantyl)5-fluorospiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate following aprocedure analogous to Example 2. LC-MS Method 4 t_(R)=2.111 min,m/z=385.2; ¹H NMR (CD₃OD) δ=1.60-1.71 (m, 2H), 1.75-1.85 (m, 8H),1.90-2.11 (m, 8H), 2.91-328 (m, 2H), 3.91 (m, 2H), 4.25 (s, 2H), 4.85(m, 1H), 7.19-7.25 (m, 1H), 7.31-7.38 (m, 1H), 7.48-7.51 (m, 1H).

Example 22 2-Adamantyl5-methylspiro[indoline-3,4′-piperidine]-1′-carboxylate

The title compound was prepared from 1-tert-butyl 1′-(2-adamantyl)5-methylspiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate following aprocedure analogous to Example 2. LC-MS Method 4 t_(R)=1.958 min,m/z=381.2; ¹H NMR (CD₃OD) δ=1.66 (m, 4H), 1.75 (m, 1H), 1.79 (m, 8H),1.90 (d, 2H), 2.11 (m, 4H), 2.21 (m, 1H), 2.32 (m, 3H), 2.95-3.22 (m,2H), 3.44 (m, 2H), 4.05-4.20 (m, 2H), 6.61 (d, 1H), 6.85 (d, 2H).

Example 23 2-Adamantyl1-acetylspiro[indoline-3,4′-piperidine]-1′-carboxylate

A procedure analogous to that described Example 7 was followed using2-adamantyl spiro[indoline-3,4′-piperidine]-1′-carboxylate. LC-MS Method5 t_(R)=2.874 min, m/z=431.1; ¹H NMR (CD₃OD) δ=1.68 (m, 5H), 1.74-1.95(m, 1H), 2.06 (m, 5H), 2.32 (s, 3H), 3.13 (br, 2H), 4.11 (s, 2H), 4.23(s, 2H), 7.08 (m, 1H), 7.22 (m, 2H), 8.11 (m, 1H).

Example 24 (±)-2-Adamantyl3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

Step 1

To a solution of(±)-2-(1′-(tert-butoxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (200 mg, 0.579 mmol) in methanol (2 mL) was added dropwise SOCl₂(137.43 mg, 1.158 mmol) at 0° C. The above mixture was allowed to stirat rt overnight. LC-MS showed that the starting material was consumedcompletely. The mixture was evaporated to give (±)-methyl2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (140.8 mg,94%). ¹H NMR (400 MHz, CD₃OD): δ=1.65 (m, 1H), 1.70-1.90 (m, 3H), 2.32(m, 1H), 2.50 (m, 1H), 2.67 (m, 1H), 2.96 (m, 1H), 3.12-3.30 (m, 2H),3.34-3.50 (m, 2H), 2.66 (m, 1H), 3.72 (s, 3H), 7.24 (m, 4H).

Step 2

To a solution of the 2-adamantyl chloroformate (144.04 mg, 0.671 mmol)and TEA (135.5 mg, 1.342 mmol) in anhydrous CH₂Cl₂ (2 mL) was added(±)-methyl dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate-(174 mg,0.671 mmol) at 0° C. in several portions. The above mixture was allowedto stir at rt overnight. LC-MS showed that the starting material wasconsumed completely. The mixture was evaporated to give a residue, whichwas purified by preparative HPLC to afford (±)-2-adamantyl3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(101 mg, 34%). ¹H NMR (400 MHz, CD₃OD): δ=1.48-1.69 (m, 614), 1.70-2.01(m, 8H), 2.06-2.1.2 (m, 5H), 2.39-251 (m, 1H), 2.62-2.73 (m, 1H),2.85-3.21 (m, 3H), 3.55-3.65 (m, 1H), 3.75 (m, 3H), 4.05-4.20 (m, 2H),4.81 (m, 1H), 7.18 (m, 4H).

Example 252-(1′-((2-Adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

2-adamantyl-3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(26 mg, 0.06 mmol) was dissolved in MeOH (1 mL) in an ice-water bath. Asolution of LiOH.H₂O (4.99 mg, 0.119 mmol) in water (0.2 mL) was addeddropwise and the mixture was stirred for 8 h at rt. LC-MS showed thatthe starting material was consumed completely. The mixture wasevaporated to give a residue, which was purified by preparative HPLC toafford2-(1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (12.2 mg, 48%). ¹H NMR (400 MHz, CD₃OD): δ=0.91 (m, 2H), 1.32 (m,3H)_(;) 1.53-1.71 (m, 6H), 1.75-1.93 (m, 8H), 1.93-2.18 (m, 4H), 2.24(m, 1H), 2.63 (m, 1H), 2.77 (m, 1H), 2.96-3.24 (br, 2H), 3.62 (m, 1H),4.10-4.28 (br, 2H), 4.72 (s, 1H), 7.15 (m, 3H), 7.24 (m, 1H).

Example 26 (±)-2-Adamantyl3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

(±)-2-Adamantyl3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(33 mg, 0.075 mmol) was added to a solution of methylamine in alcohol (2mL) at 0° C. The above mixture was heated under reflux overnight. LC-MSshowed that the starting material was consumed completely. The mixturewas evaporated to give a residue, which was purified by preparative HPLCto obtain (±)-2-adamantyl3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(12 mg, 37%). ¹H-NMR (400 MHz, CD₃OD): 8=-1.52-1.67 (m, 6H), 1.84 (m,6H), 1.93 (m, 2H), 2.07 (M, 5H), 2.28 (m, 1H), 2.56 (m, 1H), 2.77 (m,4H), 3.12 (br, 2H), 3.62 (m, 1H), 4.19 (br, 2H), 7.18 (m, 4H).

Example 27N-(2-Adamantyl)-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide

Step 1

To a solution of 2-aminoadamantane hydrochloride (126 mg, 0.68 mmol) andDIEA (872 mg, 6 mmol) in anhydrous CH₂Cl₂ (3 mL) was added CDT (120 mg,0.74 mmol) at 0° C. and stirred for 1 h at 0° C. Thenspiro[indene-2,3′-piperidin]-1(3H)-one (136 mg, 0.68 mmol) in anhydrousCH₂Cl₂ (2 mL) was added dropwise to the above mixture at 0° C. Thereaction mixture was stirred overnight under nitrogen at rt. Thereaction mixture was evaporated to give a residue, which was purified bypreparative TLC and then by preparative HPLC to affordN-(2-adamantyl)-1-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide(32 mg, 12%). ¹HNMR (CD₃OD, 400 MHZ): δ=1.51˜1.75 (m, 3H), 1.76˜1.81 (m,4H), 1.82-2.01 (m, 11H), 3.00 (m, 3H), 3.22 (m, 3H), 3.72 (m, 2H), 4.03(m, 1H), 7.41 (m, 1H), 7.53 (m, 1H), 7.71 (m, 2H).

Step 2

To a solution ofN-(2-adamantyl)-1-oxo-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide(3.0 mg, 0.079 mmol) in MeOH (3 mL) was added NaBH₄ (12 mg, 0.317 mmol)at 0° C. under nitrogen. The reaction mixture was stirred for 4 h underN₂ at rt. The reaction mixture was evaporated to give a residue, whichwas purified by preparative HPLC to affordN-(2-adamantyl)-1-hydroxy-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide(12 mg, 40%). ¹HNMR (CD₃OD, 400 MHZ): δ=1.51-1.75 (m, 5H), 1.78˜1.81 (m,4H), 1.82˜2.00 (m, 11H), 2.50 (m, 1H), 3.00 (d, 1H), 3.20 (m, 1H), 3.55(m, 1H), 3.65 (m, 1H), 3.81 (s, 1H), 4.75 (s, 1H), 7.22 (m, 3H), 7.388(m, 1H).

Step 3

To a solution ofN-(2-adamantyl)-1-hydroxy-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide(20 mg, 0.052 mmol) in ethanol (3 mL) was added Pd(OH)₂ (10 mg), thenthe reaction mixture was stirred for 4 h at rt under a hydrogenatmosphere. The reaction mixture was filtered and the filtrate wasevaporated to give a residue, which was purified by preparative HPLC toaffordN-(2-adamantyl)-1,3-dihydrospiro[indene-2,3′-piperidine]-1′-carboxamide(5 mg, 29%): LC-MS Method 5 t_(R)=3.057 min, m/z=365.2; ¹H NMR (CD₃OD,400 MHz): δ=1.55 (m, 2H), 1.66 (m, 2H), 1.78 (m, 7H), 1.84 (m, 7H),2.69-2.83 (m, 4H), 3.21 (s, 2H), 3.45 (m, 2H), 3.77 (s, 1H), 7.09 (m,2H), 7.14 (m, 2H).

Example 28N-(2-Adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using 2,3-dihydrospiro[indene-1,4′-piperidine].LC-MS Method 5 t_(R)=1.946 min, m/z=365; NMR (CD₃OD) δ=1.54 (d, 2H),1.63 (d, 2H), 1.72-2.02 (m, 14H), 2.14 (m, 2H), 2.94 (m, 2H), 3.09 (m,2H), 3.87 (m, 1H), 4.03 (d, 2H), 4.61 (s, 1H), 5.79 (m, 1H), 7.12-7.20(m, 4H).

Example 29

Tert-butyl1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 1 using tert-butyl1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate. LC-MS Methodt_(R)=3.036 min, m/z=480.3; NMR (CDCl₃) δ=1.49 (s, 9H), 1.64 (m, 7H),1.76 (m, 5H), 1.86 (m, 7H), 1.95-2.03 (m, 4H), 3.06-3.21 (m, 2H), 3.71(m, 2H), 3.91 (m, 2H), 3.99 (s, 1H), 4.62 (s, 2H), 4.82 (m, 1H), 7.08(m, 1H), 7.19 (m, 2H), 7.35 (m, 1H).

Example 30N-(2-Adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide

The title compound was prepared from tert-butyl1′4(2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylatefollowing a procedure analogous to that described in Example 2. LC-MSMethod 4 t_(R)=1.741 min, m/z=380.3; ¹H NMR (CDCl₃) δ=1.66-1.79 (m, 7H),1.79-2.01 (m, 11H), 2.17 (m, 2H), 3.14 (m, 2H), 3.58 (m, 2H), 3.93 (m,3H), 4.41 (s, 2H), 5.86-6.19 (br, 5H), 7.12 (d, 1H), 7.32 (m, 1H), 7.44(m, 2H).

Example 312-Acetyl-N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamidefollowing a procedure analogous to that described in Example 7. LC-MSMethod 4 t_(R)=2.931 min, m/z=422.2; ¹H NMR (CD₃OD) δ=1.33 (m, 1H),1.54-1.68 (m, 4H), 1.86 (m, 10H), 1.95-2.08 (m, 7H), 2.24 (d, 3H), 3.19(m, 2H), 3.81-3.98 (m, 5H), 7.17-7.24 (m, 3H), 7.39 (m, 1H).

Example 32 Ethyl3-(1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)propanoate

To a solution of 2-adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (40mg, 0.11 mmol) and TEA (37 mg, 0.32 mmol) in CH₂Cl₂ (2 mL) was dropwisea solution of acrylic acid ethyl ester (13 mg, 0.13 mmol) in CH₂Cl₂slowly at 0° C. under nitrogen atmosphere. The mixture was stirred at rtovernight. The mixture was concentrated to give the crude product, whichwas purified by preparative TLC followed by preparative HPLC to affordethyl3-(1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)propanoate(4 mg, yield: 7%). LC-MS Method 4 t_(R)=5.21 min, m/z=481.3; ¹H NMR(CD₃OD, 400 MH_(z)): δ=1.25 (m, 4H), 1.58 (m. 5H), 1.72 (m, 3H), 1.84(m, 7H), 1.88-2.17 (m, 5H), 2.53-2.92 (m, 6H), 2.94-3.22 (m, 2H), 3.68(s, 1H), 4.09-4.17 (m, 4H), 4.88 (s, 1H), 7.02 (d, 1H), 7.10-7.26 (m,2H), 7.32 (d, 1H).

Example 333-(1′-((2-Adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)propanoicacid

The title compound was prepared using a method analogous to that ofExample 6. LC-MS Method 4 t_(R)=4.78 min, m/z=453.3; ¹H NMR (CD₃OD)δ=1.72 (m, 2H), 1.86-1.97 (m, 8H), 2.01 (m, 2H), 2.04-2.17 (m, 6H), 2.95(m, 2H), 3.18 (m, 1H), 3.53-3.61 (m, 3H), 3.73 (s, 2H), 4.22 (m, 2H),4.45 (s, 2H), 7.24 (m, 1H), 7.34 (m, 1H), 7.46 (m, 1H), 7.56 (m, 1H).

Example 34N-(2-Adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide

A vial, equipped with a flea stir bar, was charged with methanesulfonylchloride (4.5 μL, 58 μmol), DIEA (15 μL, 90 μmol) and CH₂Cl₂ (1 mL). Asolution ofN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide(25 mg, 53 μmol) in CH₂Cl₂ (1 mL) was added and the mixture was stirredovernight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL)and allowed to stand for 5 min. The reaction mixture was applied to thecartridge and eluted with ether (20 mL). The eluate was evaporated todryness and the residue was purified by preparative HPLC to affordN-(2-adamantyl)-2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide(8 mg, 33%). LC-MS Method 1 t_(R)=1.89 min, =458; ¹H NMR (CDCl₃)δ=1.60-2.15 (18H), 2.92 (s, 3H), 3.13 (m, 2H), 3.51 (s, 2H), 3.90 (d,2H), 3.99 (s, 1H), 4.45 (s, 2H), 4.88 (1H), 7.05-7.40 (4H).

Example 35N1′-(2-Adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide

A vial was charged withN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide(15 mg, 40 μmol), i-Pr2NEt (11 μL, 60 μmol) and CH₂Cl₂ (1 mL). Methylisocyanate (3 μL, 43 μmol) was added and the mixture was stirredovernight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl(6 mL) and allowed to stand for 5 min. The reaction mixture was appliedto the cartridge and eluted with ether (20 mL). The eluate wasevaporated to dryness and the residue was purified by preparative HPLCto affordN1′(2-adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide(7.7 mg, 44%). LC-MS Method 1 t_(R)=1.77 min, m/z=437; ¹H NMR (CDCl₃)δ=1.60-2.10 (18H), 2.80 (1H), 2.88 (s, 3H), 3.25 (m, 2H), 3.77 (s, 2H),3.88 (d, 2H), 3.98 (s, 1H), 4.52 (s, 2H), 4.87 (1H), 7.05-7.40 (4H).

Example 36 Ethyl1′-((2-adamantyl)carbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 35 using ethyl chloroformate instead of methylisocyanate. LC-MS Method 1 t_(R)=2.1 min, m/z=452; ¹H NMR (CDCl₃) δ=1.30(t, 3H), 1.60-2.10 (18H), 3.20 (m, 2H), 3.77 (2H), 3.90 (d, 2H), 3.99(s, 1H), 4.20 (m, 2H), 4.66 (s, 2H), 4.85 (s, 1H), 7.05-7.40 (4H).

Example 37 2-Tert-butyl 1′-(2-adamantyl)1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxylate

Tert-butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate (199mg, 0.659 mmol) and i-Pr₂NEt (139 μL, 1.25 equiv.) were dissolved inCH₂Cl₂ (10 mL) and stirred for 1.5 h at rt. LC-MS showed the reactionwas complete. The mixture was diluted with ether (50 mL), washed with 3%aq HCl (2×15 mL), satd aq NaHCO₃ (15 mL) and brine (10 mL), and driedover Na₂SO₄. Filtration and concentration afforded 2-tert-butyl1′-(2-adamantyl)1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxylate (246 mg,80.5%) as a white foam-like solid. LC-MS Method 1 t_(R)=2.59 min,m/z=503; ¹H NMR (CDCl₃) δ=7.34 (t, 1H), 7.20 (m, 2H), 7.09 (d, 1H), 4.88(t, 2H), 4.62 (s, 2H), 4.16 (d, 2H), 3.72 (s, 1H), 3.25-3.03 (m, 2H),1.50 (s, 9H).

Example 38 2-Adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate

2-Tert-butyl 1′-(2-adamantyl)1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxylate (35 mg,0.073 mmol) was dissolved in 1:2 TFA/CH₂Cl₂ (6 mL) and stirred for 30min at rt. The mixture was concentrated to afford crude 2-adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (29mg, quant). LC-MS Method 1 t_(R)=1.48 min, m/z=381; ¹H NMR (CD₃OD)δ=7.52 (d, 1H), 7.38 (t, 1H), 7.28 (t, 1H), 7.21 (d, 1H), 4.85 (s, 1H),4.38 (s, 2H), 4.19 (m, 2H), 3.68 (s, 2H), 3.28-3.01 (m, 2H).

Example 39 2-Adamantyl2-(methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate

The title compound was prepared from 2-adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylatefollowing a procedure analogous to that described in Example 34. LC-MSMethod 1 t_(R)=2.16 min, m/z=459; ¹H NMR (CDCl₃) δ=7.37 (d, 1H), 7.28(t, 1H), 7.21 (t, 1H), 7.08 (d, 1H), 4.88 (s, 1H), 4.45 (br s, 2H), 4.18(d, 2H), 3.12 (br s, 2H), 2.92 (s, 3H).

Example 40 2-Adamantyl2-(isopropylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate

The title compound was prepared from 2-adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylatefollowing a procedure analogous to that described in Example 34 usingisopropylsulfonyl chloride in place of methanesulfonyl chloride. LC-MSMethod 1 t_(R)=2.31 min, m/z=487; ¹H NMR (CDCl₃) δ=7.36 (d, 1H), 7.26(t, 1H), 7.20 (t, 1H), 7.05 (d, 1H), 4.88 (s, 1H), 4.56 (br s, 2H), 4.18(d, 2H), 4.35 (m, 1H), 2.99 (m, 4H), 1.42 (d, 6H).

Example 41 2-Adamantyl2-(5-cyanopyridin-2-yl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate

Crude 2-adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (21mg, 0.054 mmol), 6-chloro-3-pyridine carbonitrile (11 mg, 1.5 equiv.)and DIEA (20 μL, 2 equiv.) were dissolved in dry DMF (1.5 mL). Themixture was heated in microwave oven for 20 min at 150° C. The mixturewas diluted with ether (10 mL), washed with 3% aq HCl (2×4 mL),concentrated and purified by preparative HPLC to afford 2-adamantyl2-(5-cyanopyridin-2-yl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate(9.5 mg, 37%). LC-MS Method 1 t_(R)=2.48 min, m/z=483; ¹H NMR. (CDCl₃)δ=8.67 (br s, 1H), 8.50 (d, 1H), 7.76 (m, 1H), 7.41 (dd, 1H), 7.30 (m,1H), 7.21 (d, 1H), 6.78 (m, 1H), 4.89 (s, 1H), 4.73 (s, 2H), 4.13 (d,4H), 3.31 (t, 2H).

Example 42 (±)-Ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

To a solution of ethyl2-(7-bromo-1′-(2-adamantylcarbamoyl)spiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate(4 g, 8 mmol) in EtOH (50 mL) was added PtO₂ (400 mg) at rt under N₂.Then the reaction mixture was stirred at rt for 6 h under H₂. Thereaction mixture was filtered and the filtrate was concentrated to leavecrude (±)-ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate.

Preparative HPLC followed by chiral HPLC afforded the two enantiomers.

Isomer 1 (1.0 g, 25%): ¹H NMR (CD₃OD): δ=1.23 (t, 3H), 1.38 (m, 2H),1.62 (d, 2H), 1.72 (m, 1H), 1.78 (m, 8H), 1.95 (m, 4H), 2.42 (m, 2H),2.86 (m, 1H), 3.06 (m; 3H), 3.59 (m, 1H), 3.86 (m, 1H), 4.14 (m, 2H),4.18 (m, 2H), 7.06 (m, 1H), 7.19 (m, 1H), 7.36 (m, 1H).

Isomer 2 (1.0 g, 25%): ¹H NMR (CD₃OD): δ=1.23 (t, 3H), 1.38 (m, 2H),1.62 (d, 2H), 1.72 (m, 1H), 1.78 (m, 8H), 1.95 (m, 4H), 2.42 (m, 2H),2.86 (m, 1H), 3.06 (m, 3H), 3.59 (m, 1H), 3.86 (m, 1H), 4.14 (m, 2H),4.18 (m, 2H), 7.06 (m, 1H), 7.19 (m, 1H), 7.37 (m, 1H).

The title compound was also prepared from (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 66 Step 1.LC-MS Method 5 t_(R)=1.761 min, m/z=531.1; ¹H NMR (CDCl₃) δ=1.21-1.31(m, 3H), 1.40-1.50 (m. 2H), 1.64-1.80 (m, 7H), 1.80-1.90 (m, 6H), 1.94(m, 2H), 2.35-2.53 (m, 3H), 2.53-2.80 (m, 8H), 2.80-2.92 (m, 2H),2.98-3.19 (m, 3H), 3.45-3.64 (m, 2H), 3.89-4.01 (m, 3H), 4.20 (m, 2H),7.05-7.15 (m, 2H), 7.40 (m, 1H).

Example 43(±)-2-(7-Bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

To a solution of ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (1.49 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH.H₂O(15 mL, 30 mmol) at 0° C. and the mixture was stirred overnight at rt.The reaction mixture was washed with 1N aq HCl until pH=5-6. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to afford2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 1 (1.27 g, 90%). LC-MS Method 5 t_(R)=1.435 min, m/z=503.2;¹H NMR (CDCl₃): δ=1.48-1.57 (m, 2H), 1.68 (m, 3H), 1.69-1.88 (m, 9H),1.93 (m, 2H), 2.49-2.52 (m, 2H), 2.63-2.72 (m, 1H), 2.89-3.17 (m, 4H),3.52-3.67 (m, 1H), 3.89-4.04 (m, 3H), 4.91 (m, 1H), 7.03-7.18 (m, 2H),7.39 (m, 1H).

To a solution of ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate,isomer 2 (1.57 g, 3 mmol) in ethanol (15 mL) was added 2 M aq LiOH.H₂O(15 mL, 30 mmol) at 0° C. and the mixture was stirred overnight at rt.The reaction mixture was washed with 1 aq N HCl until pH=5-6. Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated to obtain2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 2 (1.33 g, 90%). LC-MS Method 5 t_(R)=1.44 min, m/z=503.1;¹H NMR (CD₃OD): δ=1.19-1.48 (m, 2H), 1.48-1.62 (m, 4H), 1.65-1.95 (m,12H), 2.20-2.66 (m, 3H), 2.70-3.12 (m, 4H), 3.50 (m, 1H), 3.70-4.08 (m,3H), 4.89 (m, 1H), 6.90-7.15 (m, 2H), 7.40 (m, 1H).

Application of a similar procedure to (±)-ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateafforded(±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid. LC-MS Method 5 t_(R)=1.419 min, m/z=503; ¹H NMR (CD₃OD)δ=1.37-1.46 (m, 2H), 1.60-1.68 (m, 2H), 1.71-1.80 (m, 1H), 1.82-1.91 (m,8H), 1.91-2.06 (m, 5H), 2.40-2.50 (m, 2H), 2.70-2.81 (m, 1H), 2.93 (m,1H), 3.00-3.15 (m, 3H), 3.56-3.67 (m, 1H), 3.88 (s, 1H), 4.05-4.12 (d,2H), 7.11 (m, 1H), 7.22 (d, 1H), 7.39 (d, 1H).

Example 44(±)-N-(2-Adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

To a stirred mixture of(±)-2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (33 mg, 78 μmol), DMAP (14.3 mg, 117 μmol) and EDC.HCl (21 mg, 117μmol) in CH₂Cl₂ (3 mL) was added methanesulfonamide (7.4 mg, 78 μmol).The mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge waswetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. Thereaction mixture was applied to the cartridge and eluted with ether (40mL). The eluate was evaporated to leave a white solid (34 mg).Preparative HPLC afforded(±)-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(25.4 mg, 65%). LC-MS Method 1 t_(R)=1.85 min, m/z=500; ¹H NMR (CDCl₃)δ=1.45-2.10 (21H), 2.55 (m, 2H), 3.07 (m, 1H), 3.33 (s, 3H), 3.77 (m,2H), 3.95 (s, 1H), 4.02 (d, 1H), 4.90 (1H), 7.10-7.30 (4H), 9.70 (1H).

Example 45(±)-3-(Cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

A solution of trifluoroacetic anhydride (39 mg, 0.18 mmol) in dioxane (2mL) was added dropwise to a stirred, ice-cooled solution of(±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(60 mg, 0.14 mmol) and pyridine (63 mg, 0.28 mmol). The reaction mixturewas stirred at rt overnight. The mixture was diluted with water andextracted with EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄, and concentrated. The crude product was purified bypreparative TLC to afford(±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(10 mg, 18%). LC-MS Method 5 t_(R)=1.508 min, m/z=404.2; ¹H NMR (CDCl₃)δ=1.60-1.73 (m, 5H), 1.77-1.82 (m, 5H), 1.85-1.94 (m, 2H), 2.07-2.14 (m,1H), 2.51-2.62 (m, 3H), 2.71-2.83 (m, 114), 2.98-3.10 (m, 2H), 3.46-3.55(m, 1H), 3.82-3.94 (m, 3H), 7.10-7.15 (m, 1H), 7.20-7.28 (m, 3H).

Example 46(±)-3-((1H-Tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

To a solution of(±)-3-(cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(30 mg, 0.075 mmol) in toluene (2 mL), Me₃SnN₃ (80 mg, 0.375 mmol) wasadded. The reaction mixture was stirred at 80° C. overnight. The mixturewas concentrated. The crude product was purified by preparative HPLC toafford(±)-3-((1H-tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(15 mg, 45%). LC-MS Method 5 t_(R)=1.28 min, m/z=447.3; ¹H NMR (CD₃OD):δ=1.62-1.69 (m, 2H), 1.71-1.86 (m, 4H), 1.89-2.24 (m, 13H), 2.56-2.68(m, 1H), 3.09-3.29 (m, 3H), 3.49 (s, 1H), 3.66-3.74 (m, 1H), 3.1-3.90(m, 1H), 3.99 (s, 1H), 4.09-4.21 (m, 2H), 7.27 (d, 1H), 7.30-7.49 (m,3H).

Example 47 (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared from (±)-ethyl2-(7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 53. LC-MSMethod 6 t_(R)=1.301 min, m/z=465.2; ¹H NMR (CDCl₃) δ=1.22-1.34 (m, 3H),1.48-1.70 (m, 9H), 1.70-1.79 (m, 4H), 1.82 (m, 8H), 1.93 (m, 2H),2.00-2.13 (m, 1H), 2.37 (m, 1H), 2.47 (s, 3H), 2.53-2.70 (m, 2H),2.89-3.01 (m, 2H), 3.09 (m, 1H), 3.48-3.59 (m, 1H), 3.87-4.01 (m, 3H),4.16-4.22 (m, 2H), 4.98 (br, 1H), 6.94-7.02 (m, 2H), 7.13 (m, 1H).

Example 48(±)-2-(1′-((2-Adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from (±)-ethyl2-(1′-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 43. LC-MSMethod 5 t_(R)=1.37 min, m/z=437.3; ¹H NMR (CDCl₃) δ=1.45-1.58 (m, 3H),1.59-1.67 (m, 2H), 1.67-1.75 (m, 4H), 1.76-1.84 (m, 6H), 1.85-1.93 (m,2H), 1.98-2.10 (m, 1H), 2.37 (s, 3H), 2.40-2.47 (m, 1H), 2.50-2:69 (m,2H), 2.90-3.13 (m, 3H), 3.47-3.52 (m, 1H), 3.80-3.93 (m, 3H), 5.08-5.42(m, 5H), 6.92-6.98 (m, 2H), 7.06-7.12 (m, 1H).

Example 49 (±)-Ethyl2(1′-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared from (±)-ethyl2-(4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 53. LC-MSMethod 5 tR=1.741 min, m/z=465.2; ¹H NMR (CDCl₃) δ=1.19-1.31 (m, 5H),1.42-1.52 (m, 1H), 1.59-1.69 (m, 3H), 1.69-1.89 (m, 8H), 1.93 (m, 4H),1.99-2.08 (m, 1H), 2.17-2.29 (m, 2H), 2.32 (s, 3H), 2.84-2.94 (m, 1H),2.94-3.11 (m, 2H), 3.71 (m, 2H), 3.84-3.99 (m, 3H), 4.13-4.22 (m, 2H),7.05-7.16 (m, 2H), 7.18 (m, 1H).

Example 50(±)-2-(1′-((2-Adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from (±)-ethyl2-(1′-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 43. LC-MSMethod 5 tR=1.413 min, m/z=437.2; ¹H NMR (CDCl₃) δ=1.24 (m, 2H),1.44-1.54 (d, 1H), 1.59-1.69 (m, 4H), 1.71-1.99 (m, 9H), 2.01-2.15 (m,3H), 2.21-2.29 (m, 1H), 2.34 (m, 4H), 2.92-3.01 (m, 1H), 3.01-3.14 (m,1H), 3.65-3.79 (m, 1H), 3.83-4.01 (m, 3H), 4.06-4.14 (m, 1H), 6.95-7.07(m, 2H), 7.17 (m, 1H).

Example 51 (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared from (±)ethyl 2-(7-chlorO-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate following aprocedure analogous to that described in Example 53. LC-MS Method 5tR=1.701 min, m/z=485.2; ¹H NMR (CD₃OD) δ=1.39 (m, 3H), 1.42 (m. 2H),1.60-1.73 (m, 3H), 1.77-2.01 (m, 12H), 2.32 (m, 1H), 2.50 (m, 1H), 2.69(m, 1H), 2.72-3.08 (m, 4H), 3.58 (m, 1H), 3.86 (s, 1H), 4.05 (m, 2H),4.15 (m, 2H), 7.15 (s, 3H).

Example 52 (±)-2-(1′-((2-Adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from (E)-ethyl2-(1′-((2-adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 43. LC-MSMethod 5 t_(R)=1.406 min, =457.2; ¹HNMR (CD₃OD) δ=1.29 (s, 2H),1.41-1.52 (m. 2H), 1.56-1.73 (m, 3H), 1.73-1.91 (m, 8H), 1.92-2.05 (m,4H), 2.31-2.50 (m, 2H), 2.69-2.80 (m, 1H), 2.87-3.00 (m, 3H), 3.02-3.15(m, 1H), 3.59 (m, 1H), 3.84 (s, 1H), 4.01-4.10 (m, 2H), 7.10-7.19 (m,3H).

Example 53 (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

A solution of 2-aminoadamantane (123 mg, 0.66 mmol), CDI (107 mg, 0.66mmol), DIEA (232 mg, 0.18 mmol) was stirred at 0° C. for 1 h. Then(±)-ethyl2-(6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (180mg, 0.60 mmol) was added to the solution and the mixture was stirred atrt overnight. The solvent was removed and the residue was purified bypreparative TLC to give (±)-ethyl2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(250 mg, 86%). LC-MS Method 6 t_(R)=1.492 min, m/z=485.2; ¹H NMR(CDCl₃): δ=1.29 (t, 3H), 1.56-1.66 (m, 4H), 1.66-1.80 (m, 6H), 1.85 (m,5H), 1.93 (m, 2H), 2.04-2.16 (m, 1H), 2.37-2.49 (m, 1H), 2.56-2.65 (m,1H), 2.88-2.92 (m, 1H), 3.00-3.20 (m, 2H), 3.55-3.66 (m, 1H), 3.81-3.90(m, 1H), 3.90-4.00 (m, 2H), 4.20 (q, 2H), 5.26-5.50 (m, 3H), 7.07-7.14(m, 2H), 7.19 (m, 1H).

Example 54 (±)-2-(1′-((2-Adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidin]-3-yl)acetic acid

To a solution of (±)-ethyl2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(150 mg, 0.3 mmol) in MeOH (3 mL), LiOH (15 mg, 0.6 mmol) was added andthe mixture was stirred for 2 h. The solution was concentrated to givethe residue, which was purified by preparative HPLC to obtain(±)-2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (10 mg, 7%). LC-MS Method 5 t_(R)=1.485 min, m/z=457.2; ¹H NMR(CD₃OD): δ=1.59-1.76 (m, 6H), 1.86-1.99 (m, 8H), 1.99-2.19 (m, 6H),2.48-2.57 (m, 1H), 2.78 (m, 1H), 2.95 (m, 1H), 3.00-3.09 (m, 1H),3.11-3.23 (m, 1H), 3.69 (m, 1H), 3.94 (s, 1H), 4.06-4.19 (m, 2H), 7.26(m, 3H).

Example 55 (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared from (±)ethyl2-(5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 53. LC-MSMethod 5 t_(R)=2.323 min, m/z=485.2; ¹H NMR (CDCl₃) δ=1.29 (t, 3H),1.54-1.69 (m, 6H), 1.73 (m, 4H), 1.79-1.89 (m, 6H), 1.92 (m, 2H),2.04-2.16 (m, 1H), 2.36-2.47 (m, 1H), 2.56-2.63 (m, 1H), 2.82-2.90 (m,1H), 2.99-3.19 (m, 2H), 3.34-3.58 (m, 4H), 3.60 (m, 2H), 3.81-3.89 (m,1H), 3.94 (m, 2H), 4.16-4.24 (m, 2H), 7.08 (d, 1H), 7.13 (s, 1H), 7.22(d, 1H).

Example 56(±)-2-(1′-((2-Adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from (±)-ethyl2-(1′-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 54. LC-MSMethod 5 t_(R)=1.442 min, m/z=457.2; ¹H NMR (CDCl₃) δ=1.21-1.32 (m, 4H),1.43 (m, 1H), 1.49-1.70 (m, 6H), 1.72-1.91 (m, 10H), 1.88-2.11 (m, 3H),2.42-2.51 (m, 1H), 2.64 (m, 1H), 2.8.5-3.11 (m, 4H), 3.56-3.67 (m, 1H),3.82-4.00 (m, 3H), 4.80-4.91 (m, 1H), 6.99-7.10 (m, 1H), 7.11-7.20 (m,2H).

Example 57(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

(±)-2-(6-Methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (0.071 mmol), 2-adamantyl isocyanate (14 mg, 1 equiv) and i-Pr₂NEt(37 μL, 3 equiv.) were dissolved in CH₂Cl₂ (3 mL) and put on a shakerfor 1 h at rt. The mixture was diluted with EtOAc (10 mL), washed with3% aq HCl (2×4 mL), concentrated and purified by preparative HPLC toafford(±)-2-(1′-((2-adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (20.4 mg, 66% yield). LC-MS Method 1 t_(R)=1.93 min, m/z=437; 1HNMR (CDCl3) 7.05 (q, 2H), 6.96 (s, 1H), 4.94 (br s, 1H), 3.98 (s, 2H),3.89 (d, 1H), 3.59 (m, 1H), 3.10-2.93 (m, 3H), 2.63 (dd, 1H), 2.43 (dd,1H), 2.33 (s, 3H), 2.09 (td, 1H).

Example 58(±)-2-(1′-((2-Adamantyl)carbamoyl)-5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from(±)-2-(5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 57.LC-MS Method 1 t_(R)=1.94 min, m/z=437; ¹H NMR (CDCl₃) δ=7.05 (s, 2H),7.00 (s, 1H), 4.90 (br s, 1H), 3.99 (s, 2H), 3.89 (d, 2H), 3.61 (m, 1H),3.10-2.93 (m, 3H), 2.63 (dd, 1H), 2.44 (dd, 1H), 2.33 (s, 3H), 2.08 (td,1H).

Example 59(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-methoxy-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from(±)-2-(6-methoxy-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 57.LC-MS Method 1 t_(R)=1.83 min, m/z=453; ¹H NMR (CDCl₃) δ=7.05 (d, 1H),6.78 (dd, 1H), 6.73 (d, 1H), 4.97 (br s, 1H), 3.97 (s, 2H), 3.88 (d,1H), 3.78 (s, 3H), 3.61 (m, 1H), 3.11-2.92 (m, 3H), 2.62 (dd, 1H), 2.46(dd, 1H), 2.05 (td, 1H).

Example 60(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from(±)-2-(6-fluoro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 57.LC-MS Method 1 t_(R)=1.87 min, m/z=441; ¹H NMR (CDCl₃) δ=7.13 (dd, 6.90(td, 1H), 6.83 (dd, 1H), 3.97 (m, 2H), 3.90 (d, 1H), 3.60 (m, 1H),3.14-2.90 (m, 3H), 2.65 (dd, 1H), 2.47 (dd, 1H), 2.04 (td, 1H).

Example 61 (±)-Ethyl2-(7-bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate

The title compound was prepared from (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and1-adamantyl isocyanate following a procedure analogous to that describedin Example 57. LC-MS Method 1 tR=2.32 min, m/z=531; ¹H NMR (CDCl₃)δ=7.38 (d, 1H), 7.12-7.04 (m, 2H), 4.19 (q, 2H), 3.87 (m, 2H), 3.57 (m,1H), 3.13-2.83 (m, 4H), 2.63 (dd, 1H), 2.44 (m, 2H), 1.42 (d, 2H), 1.29(t, 3H).

Example 62(±)-2-(7-Bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from (±)-ethyl2-(7-bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 54. LC-MSMethod 1 t_(R)=1.99 min, m/z=503; ¹H NMR (CDCl₃) δ=7.40 (d, 1H),7.16-7.06 (m, 2H), 3.87 (m, 2H), 3.59 (m, 1H), 3.17-2.93 (m, 4H), 2.68(dd, 1H), 2.48 (m, 2H), 1.44 (d, 2H).

Example 63(±)-2-(7-Bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

Step 1

A 100-mL of flask was charged with (±)-tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(500 mg, 1.1 mmol) dissolved in 20% TFA in CH₂Cl₂ solution (15 mL) at 0°C. The mixture was stirred for 0.5 h at 0° C. Then the mixture wasconcentrated to give crude (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate whichwas used in the next step without further purification.

Step 2

A 100-mL flask was charged with (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (457mg, 1.3 mmol) dissolved in dry CH₂Cl₂ (10 mL). TEA (394 mg, 3.9 mmol)was added at 0° C. and stirred for 1 h. 2-adamantyl chloroformate (301mg, 1.4 mmol) was added and the mixture was stirred overnight. Themixture was concentrated to give a residue was purified by columnchromatography to give (±)-(2-adamantyl)7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(270 mg, 39%). The enantiomers were separated by chiral HPLC to giveisomer 1 (100 mg, 14%) and isomer 2 (100 mg, 14%).

Step 3

A 25-mL of flask was charged with (2-adamantyl)7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylateisomer 1 (100 mg, 0.19 mmol) dissolved in MeOH (3 mL). LiOH (10 mg, 0.38mmol) dissolved in H₂O (3 mL) was added and the mixture was stirred for2 h at it. The mixture was concentrated to remove MeOH. The aqueouslayer was acidified with 1 N aq HCl (5 mL) and extracted with EtOAc (3×5mL). The organic layers were combined, washed with brine, dried overNa₂SO₄, filtered and concentrated to give2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 1 (45 mg, 47%). LC-MS Method 5 tR=1.604 min, m/z=504.1; ¹HNMR (CD₃OD): δ=1.26 (m, 1H), 1.37 (d, 2H), 1.61-2.09 (m, 15H), 2.41 (m,2H), 2.72 (m, 1H), 1.39 (m, 1H), 3.01-3.22 (m, 3H), 3.55 (m, 1H);4.11-4.29 (b, 2H), 7.06 (m, 1H), 7.20 (d, 1H), 7.36 (d, 1H).

(2-Adamantyl)7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylateisomer 2 was converted to2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 2 using a similar procedure. LC-MS Method 5 t_(R)=1.604 min,m/z=502.1; ¹H NMR (CD₃OD) δ=1.37 (d, 2H), 1.62 (d, 3H), 1.70-1.95 (m,8H), 2.05 (m, 4H), 2.40 (m, 2H), 2.70 (m, 114), 2.87 (m, 1H), 2.92-3.20(b, 2H), 3.55 (m, 1H), 4.10-4.30 (b, 2H), 7.05 (m, 1H), 7.20 (d, 1H),7.35 (d, 1H).

(±)-(2-Adamantyl)7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylatewas converted to(±)-2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid using a similar procedure. LC-MS Method 6 t_(R)=1.698 min,m/z=504.1; ¹H NMR (CDCl₃) δ=0.81-1.02 (m, 4H), 1.20-1.46 (m, 4H),1.46-1.92 (m, 1514), 1.92-2.11 (m, 4H), 2.31-2.85 (m, 5H), 2.92-3.19 (m,3H), 3.56-3.70 (m, 2H), 4.15-4.36 (m, 2H), 4.60-4.81 (m, 3H), 4.89 (s,1H), 7.04-7.15 (m, 2H), 7.40 (m, 1H).

Example 64(±)-2-(6-Methyl-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from2-(6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acidand 2-adamantyl chloroformate following a procedure analogous to thatdescribed in Example 57. LC-MS Method 1 t_(R)=2.24 min, m/z=438; ¹H NMR(CDCl₃) δ=7.06 (q, 2H), 6.97 (s, 1H), 4.88 (s, 1H), 4.20 (t, 2H), 3.60(m, 1H), 3.13-2.94 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.35 (s, 3H).

Example 65 (±)-2-(5-Methyl-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid

The title compound was prepared from2-(5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acidand 2-adamantyl chloroformate following a procedure analogous to thatdescribed in Example 57. LC-MS Method 1 t_(R)=2.24 min, m/z=0.438; ¹HNMR (CDCl₃) δ=7.06 (m, 2H), 7.00 (s, 1H), 4.88 (s, 1H), 4.19 (t, 2H),3.61 (m, 1H), 3.03 (m, 3H), 2.64 (dd, 1H), 2.48 (dd, 1H), 2.34 (s, 3H).

Example 662-(7-Bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoicacid

Step 1

To a solution of (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (160mg, 0.906 mmol) in dry CH₂Cl₂ was added CDI (176 mg, 1.08 mmol) and DIEA(1.16 g, 9.06 mmol) at 0° C. under N₂. The mixture was stirred for 1 h,and 2-adamantanamine hydrochloride (331 mg, 0.906) in CH₂Cl₂ was added.The reaction mixture was stirred at rt overnight. The solvent wasremoved under reduced pressure to leave a residue which was purified bypreparative TLC to give (±)-ethyl2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate(200 mg, 41%). ¹H NMR: (400 MHz, CDCl₃): δ=1.11 (s, 3H), 1.22 (s, 3H),1.26 (m, 3H), 1.45 (m, 2H), 1.52 (m, 3H), 1.73 (m, 4H), 1.85 (m, 7H),1.95 (s, 2H), 2.44 (m, 2H), 3.02-3.26 (m, 4H), 3.79 (m, 2H), 3.98 (m,3H), 4.25 (m, 2H), 6.93 (m, 1H), 7.01 (m, 1H), 7.35 (m, 1H).

Step 2

To a solution (±)-ethyl2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate(63 mg, 0.122 mmol) in anhydrous MeOH (1 mL) was added LiOH.H₂O (10 mg,0.244 mmol) in H₂O (0.1 mL). The reaction mixture was stirred at rtovernight. The mixture was concentrated to give crude product, which waspurified by preparative TLC to afford2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoicacid. ¹H NMR: (400 MHz, CDCl₃): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43(m, 2H), 1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H),2.51-2.61 (m, 1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m, 2H),7.01 (m, 1H), 7.21-7.33 (m, 2H).

Example 67 (±)-Ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate

The title compound was prepared from (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoatefollowing a procedure analogous to that described in Example 66 Step 1.LC-MS Method 5 t_(R)=1.982 min, m/z=559.1; ¹H NMR (CDCl₃) δ=1.12 (s,3H), 1.23 (s. 3H), 1.27 (m, 3H), 1.45 (m, 2H), 1.57-1.75 (m, 3H), 1.79(m, 4H), 1.89 (m, 7H), 1.95 (s, 2H), 2.45 (m, 2H), 3.02-3.26 (m, 4H),3.80 (m, 2H), 3.92 (m, 3H), 4.21 (m, 2H), 6.93 (m, 1H), 7.01 (m, 1H),7.35 (m, 1H).

Example 68 (±)-2-(7-Bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl-2-methylpropanoic acid

Step 1

To a solution of (±)-ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate(100 mg, 0.18 mmol) in anhydrous toluene was added DIBAL-H (0.4 mL, 1 M)at −78° C. The mixture was stirred for 30 min and quenched with MeOH.The organic layer was separated, dried and concentrated to give crude(±)-7-bromo-N-(2-adamantyl)-3-(2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamidewhich was used for the next step without purification.

Step 2

To a solution of crude(±)-7-bromo-N-(2-adamantyl)-3-(2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(40 mg, 0.0778 mmol) in dry acetone was added H₂Cr₂O₇ (234 mg, 0.8mmol), and the solution was stirred for 1 h. 0.5 Treatment of themixture with NaBH₄ and concentration afforded the crude product whichwas purified by preparative HPLC to give(±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoicacid (1.55 mg, 5%). LC-MS Method 5 t_(R)=1.504 min, m/z=531; ¹H NMR:(400 MHz, CDCl₃): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43 (m, 2H),1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H), 2.51-2.61 (m,1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m; 2H), 7.01 (m, 1H),7.21-7.33 (m, 2H).

Example 69 (±)-2-Adamantyl7-bromo-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

The title compound was prepared from2-(7-bromo-1′-(2-adamantyloxycarbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 44.LC-MS Method 5 t_(R)=1.648 min, m/z=581.1; ¹H NMR (CD₃OD) δ=1.42 (m,2H), 1.65 (m, 2H), 1.70-1.88 (m, 8H), 1.88-2.12 (m, 7H), 2.39-2.50 (m,2H), 2.74 (m, 2H), 2.94 (m, 2H), 2.97-3.15 (m, 4H), 3.64 (m, 2H),4.10-4.29 (m, 2H), 7.10 (m, 1H), 7.22 (m, 1H), 7.39 (m, 1H).

Example 70(±)-7-Bromo-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from(±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 44.LC-MS Method 5 t_(R)=1.406 min, m/z=579.9; ¹H NMR (CDCl₃) δ=1.24 (m,1H), 1.31-1.44 (m, 4H), 1.60-1.79 (m, 7H), 1.84 (m, 7H), 1.91 (m, 2H),2.51-2.65 (m, 3H), 2.85-2.99 (m, 2H), 3.00-3.18 (m, 2H), 3.31 (s, 3H),3.60-3.74 (m, 2H), 3.80 (d, 1H), 3.92-4.08 (m, 2H), 4.91 (d, 1H), 7.06(m, 1H), 7.13 (d, 1H), 7.38 (d, 1H).

Example 71

(±)-2-Adamantyl3-(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

The title compound was prepared from (±)-2-adamantyl3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylateand dimethylamine following a procedure analogous to that described inExample 26. LC-MS Method 5 t_(R)=2.959 min, m/z=473.2; ¹H NMR (CD₃OD)δ=1.56 (m, 6H), 1.83 (m, 6H), 1.93 (d, 2H), 2.04 (m, 5H), 2.51 (m, 1H),2.64 (m, 1H), 2.99 (s, 4H), 3.08 (s, 4H), 3.65 (m, 1H), 4.09-4.22 (br,2H), 7.18 (m, 4H).

Example 722-(1′-((1-(3,5-Dimethoxybenzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

Step 1

4-oxoadamantane-1-carboxylic acid (200 mg, 1.03 mol),(3,5-dimethoxyphenyl)methanamine (172 mg, 1.03 mmol), EDCI (410 mg, 2.06mmol), and HOBt (280 mg, 2.06 mmol) were dissolved in dry CH₂Cl₂. DIEA(1.3 g, 10 mmol) was added under nitrogen at 0° C. and the mixture wasstirred overnight at rt. The mixture was washed with water and brine.The organic layer was dried and concentrated to give crude product whichwas purified by preparative TLC to giveN-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide (231 mg, 65%). ¹HNMR: (400 MHz, CDCl₃): δ=1.62 (s, 4H) 1.95-2.25 (m, 13H), 2.59 (s, 2H),3.78 (s, 3H), 3.83 (s, 3H), 4.35 (d, 2H), 6.05 (s, 1H), 6.44 (m, 2H),7.15 (d, 1H).

Step 2

To a solution of N-(3,5-dimethoxybenzyl)-4-oxoadamantane-1-carboxamide(230 mg, 0.670 mol) in anhydrous CH₃OH was added NaBH₄ (100 mg, 2.7mmol) at 0° C. The reaction mixture was stirred for 1 h at rt. Thesolvent was removed under reduced pressure, diluted with CH₂Cl₂ andwashed with water. The organic layer was separated, dried, andconcentrated to giveN-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-1-carboxamide (230 mg,100%). ¹H NMR: (400 MHz, CDCl₃): δ=1.40 (d, 1H), 1.46-1.62 (m, 6H),1.70-1.82 (m, 5H), 1.84-1.95 (m, 3H) 2.01-2.14 (m, 2H), 3.75 (s, 3H),3.80 (s, 3H), 3.82 (s, 1H), 4.29 (d, 2H), 5.98 (s, 1H), 6.40 (m, 0.2H),7.08 (d, 1H).

Step 3

To a solution ofN-(3,5-dimethoxybenzyl)-4-hydroxyadamantane-1-carboxamide (210 mg, 0.608mmol) and TEA (307 mg, 3.04 mmol) in dry CH₂Cl₂ was added triphosgene(72 mg, 0.234 mmol) at 0° C. under N₂. The mixture was stirred for 1 h,and (±)-2-(2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid(130 mg, 0.608 mmol) in CH₂Cl₂ was added. The reaction mixture wasstirred overnight at rt. The solvent was removed under reduced pressure.The residue was diluted with CH₂Cl₂ and then washed with water. Theorganic layer was dried, filtered and concentrated to afford crudeproduct, which was purified by preparative TLC to give2-(1′-((1-(3,5-dimethoxybenzylcarbamoyl)4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (50 mg, 14%). LC-MS Method 5 t_(R)=1.341 min, m/z=617.1; ¹H NMR:(400 MHz, CDCl₃): δ=1.22-1.51 (m, 5H), 1.63 (s, 3H), 1.75-1.96 (m, 12H),2.08 (m, 3H), 2.22-2.38 (m, 3H), 2.60-3.12 (m, 12H) □3.41 (s, 2H),3.58-3.82 (m, 6H), 4.00 (m, 2H), 4.33 (d, 0.214), 4.74 (d, 1H), 6.11 (d,1H), 6.30-6.50 (m, 2H), 6.96-7.15 (m, 4H).

Example 732-(1′-((1-Carbamoyl-4adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

To a solution of2-(1′-((1-(3,5-dimethoxybenzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (40 mg, 0.096 mmol) was added 50% TFA (2.5 mL) at 0° C. Thereaction mixture was stirred for 4 h at rt. The TFA was neutralized, andthe solution was dried and concentrated to give crude product which waspurified by preparative HPLC to give2-(1′-((1-carbamoyl-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (2 mg, 7%). LC-MS Method 4 t_(R)=2.078 min, m/z=467.2; ¹H NMR: (400MHz, CDCl₃): δ=0.88 (m, 3H), 1.29 (m, 3H), 1.52-1.68 (m, 8H), 1.60-1.69(m, 4H), 1.78-1.94 (m, 13H), 1.95-2.10 (m, 9H), 2.19-2.30 (m, 3H), 2.46(m, 1H), 2.68 (m, 1H), 2.90-3.15 (m, 3H), 3.65 (m, 1H), 4.12-4.27 (m,2H), 4.83-4.91 (m, 1H), 5.65-5.79 (m, 1H), 7.15-7.24 (m, 4H).

Example 742-(7-Bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid, isomers 1 and 2

Step 1

To (±)-tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperi-dine]-1′-carboxylateisomer 1 (500 mg, 1.10 mmol) was added 20% TFA in CH₂Cl₂ (25 mL) at 0°C. The mixture was stirred for 1 h and concentrated to give (±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate isomer1 (498 mg, crude).

Step 2

A solution of 4-aminoadamantan-1-ol (628 mg, 3.76 mmol) in dry CH₂Cl₂ (2mL) was added CDI (736 mg, 4.52 mmol) and DIEA (3.24 g, 25.12 mmol) at0° C. under N₂ and the mixture was stirred for 1 h. Ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate (1.10g, 3.14 mmol) was added and the mixture was stirred overnight. Themixture was washed with 5% aq HCl, and the organic layer wasconcentrated to give the crude product. Purification by preparative TLCfollowed by preparative HPLC gave two isomers of ethyl2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate.

Step 3

To a solution of ethyl2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (150 mg, 0.275 mmol) in dry CH₂Cl₂ (5 mL) was added DAST (0.1mL) at −78° C. The mixture was stirred for 4 h and quenched with NaHCO₃.The mixture was extracted with CH₂Cl₂. The organic layer was dried,filtered and concentrated to give the crude product, which was purifiedby preparative TLC to give ethyl2-(7-bromo-1′-((1-fluoro-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (120 mg, 80%). ¹H NMR: (400 MHz, CDCl₃): δ=0.89 (m, 3H) □1.25(m, 3H), 1.43 (m, 2H), 1.61-1.82 (m, 9H), 1.94 (m, 4H), 2.18 (m, 1H),2.36 (m, 2H), 2.48 (m, 2H), 2.68 (m, 1H), 2.85 (m, 1H), 2.92-3.14 (m,3H), 3.60 (m, 1H), 3.88 (m, 1H), 3.95 (m, 2H), 4.20 (m, 2H), 4.70 (m,1H), 7.09 (m, 2H), 7.41 (m, 1H).

Step 4

To a solution of ethyl2-(7-bromo-1′-((1-fluoro-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateisomer 1 (120 mg, 0.22 mmol) in MeOH (6 mL) was added LiOH.H₂O (20 mg,0.44 mmol) at room temperature and the mixture was stirred overnight.The mixture was concentrated to give a residue which was extracted withEtOAc. The organic layer was dried, filtered and concentrated to givecrude product, which was purified by TLC to give2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 1 (100 mg, 88%). LC-MS Method 5 t_(R)=1.227 min, m/z=521.1;¹H NMR (CD₃OD) δ=1.39 (m, 2H), 1.65-1.80 (m, 7H), 1.83 (m, 2H),2.05-2.20 (m, 3H), 2.29 (m, 2H), 2.42 (m, 2H), 2.71 (m, 1H), 2.88 (m,1H), 2.90-3.10 (m, 3H), 3.55 (m, 1H), 3.70 (s, 1H), 4.05 (d, 2H), 7.06(m, 1H), 7.20 (d, 1H), 7.35 (d, 1H).

Isomer 2: ¹H NMR: (400 MHz, CDCl₃): δ=1.26 (m, 2H), 1.40 (m, 2H), 1.70(m, 6H), 1.86 (m, 2H), 2.12 (m, 3H), 2.22 (m, 1H), 2.34 (m, 2H), 2.46(m, 2H), 2.70 (m, 1H), 2.86-3.13 (m, 4H), 3.55 (m, 1H), 3.70 (m, 1H),4.05 (m, 2H), 7.06 (m, 1H), 7.22 (m, 1H), 7.35 (m, 1H).

Following procedures analogous to those described in Steps 3 and 4,ethyl2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatewas converted to2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomer 2. LC-MS Method 5 t_(R)=1.235 min, m/z=519.1; ¹H NMR (CD₃OD)δ=1:29 (m, 2H), 1.40 (m, 2H), 1.61 (m, 1H), 1.72-1.92 (m, 5H), 2.10 (m,3H), 2.34 (m, 2H), 2.62 (m, 1H), 2.79 (m, 1H), 2.85-3.05 (m, 3H), 3:49(m, 1H), 3.71 (s, 1H), 3.97 (d, 2H), 7.00 (m, 1H), 7.12 (d, 1H), 7.27(d, 1H).

Following procedures analogous to those described in Steps 1 to 4 butwithout separation of the isomers in Step 2, tert-butyl7-bromo-3-(2-ethoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperi-dine]-1′-carboxylateisomer 2 was converted to a mixture of2-(7-bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid isomers 3 and 4. LC-MS Method 4 t_(R)=2.347 min, m/z=519.2; ¹H NMR(CDCl₃) δ=1.46 (m, 2H), 1.56 (m. 1H), 1.73 (m, 4H), 1.82 (m, 2H), 1.93(m, 4H), 2.22-2.32 (m, 3H), 2.51 (m, 2H), 2.71 (m, 1H), 2.96 (d, 1H),3.11 (d, 1H), 3.62 (m, 1H), 3.83 (m, 1H), 3.96 (m, 3H), 7.09 (m, 1H),7.15 (m, 1H), 7.41 (m, 1H).

Example 752-(7-Bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

A mixture of isomers 1 and 2 of the title compound was prepared from amixture of isomers 1 and 2 of ethyl2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing a procedure analogous to that described in Example 66 Step 2.LC-MS Method 4 t_(R)=1.972/1.997 min, m/z=517.1; ¹H NMR (CDCl₃) δ=1.22(m, 2H), 1.36 (m, 2H), 1.43 (m, 1H), 1.52 (m, 2H), 1.65 (m, 5H), 1.82(m, 2H), 2.07 (m, 3H), 2.33-2.42 (m, 2H), 2.61 (m, 1H), 2.88 (m, 2H),2.98 (m, 2H), 3.42 (s, 2H), 3.51 (m, 1H), 3.82-3.89 (m, 2H), 7.01 (m,1H), 7.06 (m, 1H), 7.29 (m, 1H).

Isomer 3 and 4 of the title compound were prepared from a mixture ofisomers 3 and 4 of ethyl2-(7-bromo-1′-((1-hydroxy-4-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetateand separated by preparative HPLC.

Isomer 3: LC-MS Method 4 t_(R)=1.972 min, m/z=519; ¹H NMR (CDCl₃)δ=1.37-1.45 (m, 2H), 1.59-1.79 (m, 11H), 1.88 (d, 2H), 2.13 (m, 2H),2.21 (s, 2H), 2.41-2.52 (m, 2H), 2.63-2.71 (m, 1H), 2.90-3.19 (m, 4H),3.56 (m, 1H), 3.88-4.00 (m, 3H), 7.03-7.12 (m, 2H), 7.39 (d, 1H).

Isomer 4: LC-MS Method 4 t_(R)=2.007 min, m/z=519; ¹H NMR (CDCl₃)δ=1.42-1.56 (m, 4H), 1.67-1.73 (m. 2H), 1.75 (m, 6H), 1.82-1.91 (m, 2H),2.16 (m, 3H), 2.44-2.60 (m, 2H), 2.70 (m, 1H), 2.92-3.00 (m, 1H),3.00-3.22 (m, 3H), 3.58 (m, 1H), 3.82-3.99 (m, 3H), 7.06-7.16 (m, 2H),7.40 (d, 1H).

Example 76(±)-2-(7-Bromo-1′-(1,7-dihydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared from 1,7-dihydroxy-4-aminoadamantane and(±)-ethyl2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetatefollowing procedures analogous to those described in Example 74 Steps 2and 4. LC-MS Method 4 t_(R)=1.686 min, m/z=535.1; ¹H NMR (CD₃OD) δ=1.37(s, 3H), 1.40 (m. 2H), 1.48 (m, 2H), 1.69 (m, 4H), 1.75 (m, 2H), 1.90(m, 2H), 2.31 (s, 2H), 2.46 (m, 2H), 2.73 (m, 1H), 2.88 (m, 1H), 2.97(m, 1H), 3.08 (m, 2H), 3.58 (m, 1H), 3.65 (s, 1H), 4.06 (m, 2H), 7.09(m, 1H), 7.23 (m, 1H), 7.36 (m, 1H).

Example 77N-(2-Adamantyl)-6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-carboxamide

Step 1

A stirred solution of 2-adamantyl isocyanate (0.99 g, 5.6 mmol) inCH₂Cl₂ (40 mL) was cooled in an ice bath and a solution of1,5-dioxa-9-azaspiro[5,5]undecane (0.97 g, 6.1 mmol) and DIEA (2.2 mL,12.3 mmol) in CH₂Cl₂ (10 mL) was added over 2 min. The ice bath wasallowed to melt and the mixture was stirred overnight at rt. The mixturewas diluted with ether (150 mL), washed with 5% aq HCl (2×50 mL) andsatd aq NaHCO₃ (50 mL), and dried over MgSO₄. Removal of the solventleft N-(2-adamantyl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxamide(1.55 g, 83%) as a white solid.

Step 2

A stirred mixture ofN-(2-adamantyl)-1,5-dioxa-9-azaspiro[5.5]undecane-9-carboxamide (585 mg,1.75 mmol), 3-methoxyphenethylamine (0.25 mL, 1.75 mmol) and 85% H₃PO₄(5 mL) was heated at 90° C. for 20 h. The mixture was diluted with water(30 mL) and washed with ether (70 mL). The aqueous layer was basifiedwith NaOH and diluted with water to give a slurry which was extractedwith CH₂Cl₂ (2×50 mL). The combined CH₂Cl₂ extracts were washed withbrine, dried over Na₇SO₄ and concentrated to afford an amber oil (780mg). A 50 mg portion was purified by prep HPLC to affordN-(2-adamantyl)-6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-carboxamide(13 mg) as an oil. LC-MS Method 1 t_(R)=1.33 min, m/z=. 410; ¹H NMR(CDCl₃) δ=1.60-2.30 (20H), 3.10 (2H), 3.42 (2H), 3.79 (s, 3H), 3.92(2H), 3.97 (s, 1H), 5.17 (br s, 1H), 6.65 (1H), 6.82 (1H), 7.12 (1H).

Example 78N-(2-Adamantyl)-3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] following a procedureanalogous to that described in Example 1. LC-MS Method 5 t_(R)=1.781min, m/z=379.2; ¹H NMR (CD₃OD) δ=1.65 (m, 4H), 1.82 (m, 5H), 1.86 (m,5H), 1.95 (m, 6H), 2.03 (m, 2H), 2.76 (m, 2H), 3.12 (m, 2H), 3.87-4.05(m, 3H), 5.76 (m, 1H), 7.03 (m, 2H), 7.14 (m, 1H), 7.89 (m, 1H).

Example 79 (2-Adamantyl)9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate

Step 1.

Methanol (50 mL) was cooled in an ice bath and SOCl₂ (2 mL) was addeddropwise with stirring. After 15 min,2-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (0.34g, purchased from WuXi Pharmatech) was added. The mixture was stirred atrt for 2 d and concentrated to afford methyl2-(3-azaspiro[5.5]undecan-9-yl)acetate as its hydrochloride salt.

Step 2.

A vial was charged with methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetateHCl salt (31 mg, 0.12 mmol) and DIEA (45 μL, 0.25 mmol). A solution of2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH₂Cl₂ (2 mL) was addedand the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridgewas wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. Thereaction mixture was applied to the cartridge and eluted with ether (20mL). The eluate was evaporated to dryness and the residue was purifiedby preparative HPLC to afford (2-adamantyl)9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (35 mg,74%). LC-MS Method 1 t_(R)=2.52 min, m/z=404; ¹H NMR (CDCl₃) δ=1.05-2.10(27H), 2.23 (d, 2H), 3.41 (m, 4H), 3.69 (s, 3H), 4.82 (s, 1H).

Example 802-(3-((2-Adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid

(2-Adamantyl)9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (30 mg,74 μmol) was dissolved in THF (0.25 mL), water (0.25 mL) and MeOH (0.5mL) and LiOH.H₂O (8 mg, 0.19 mmol) was added. The mixture was stirred atrt for 2 d and TFA (10 mL, 0.14 mmol) was added. The solution wassubmitted directly to prep HPLC to afford2-(34(2-adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid(10.5 mg, 36%). LC-MS Method 1 t_(R)=2.17 min, m/z=390; ¹H NMR (CDCl₃)δ=1.0-2.05 (27H), 2.27 (d, 2H), 3.44 (m, 4H), 4.83 (s, 1H).

Example 81 Methyl2-(3-((2-adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetate

The title compound was prepared following a procedure analogous to thatdescribed in Example 79 using 2-adamantyl isocyanate in place of2-adamantyl chloroformate. LC-MS Method 1 t_(R)=2.15 min, m/z=403; ¹HNMR (CDCl₃) δ=1.05-2.10 (27H), 2.24 (d, 2H), 3.30 (m, 4H), 3.42 (s, 1H),3.68 (s, 3H), 4.93 (s, 1H).

Example 822-(3-((2-Adamantyl)carbamoyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid

The title compound was prepared following a procedure analogous to thatdescribed in Example 80. LC-MS Method 1 t_(R)=1.83 min, m/z=389; ¹H NMR(CDCl₃) δ=1.10-2.00 (29H), 3.33 (m, 4H), 2.27 (d, 2H), (3.93 (s, 1H).

Example 83N-(2-Adamantyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from3H-spiro[isobenzofuran-1,4′-piperidine] following a procedure analogousto that described in Example 79 Step 2 using 2-adamantyl isocyanate inplace of 2-adamantyl chloroformate. LC-MS Method 1 t_(R)=2.03 min,m/z=367; ¹H NMR (CDCl₃) δ=1.60-2.00 (18H), 3.29 (m, 2H), 3.94 (m, 2H),3.99 (s, 1H), 4.95 (1H), 5.08 (s, 2H), 7.05-7.35 (4H).

Example 84 2-Adamantyl3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate

The title compound was prepared from3H-spiro[isobenzofuran-1,4′-piperidine] following a procedure analogousto that described in Example 79. LC-MS Method 1 t_(R)=2.42 min, m/z=368;¹HNMR (CDCl₃) δ=1.50-2.10 (18H), 3.24 (m, 2H), 4.19 (m, 2H), 4.88 (s,1H), 5.09 (s, 2H), 7.05-7.35 (4H).

Example 85 1-Tert-butyl1′-(trans-1-carbamoyl-4-adamantyl)spiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate

The title compound was prepared from tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate and1-methoxycarbonyl-4-adamantyl chloroformate following proceduresanalogous to those described in Example 79 Step 2, Example 80 andExample 127. LC-MS Method 5 t_(R)=2.467 min, m/z=410.2; ¹H NMR (CD₃OD)δ=1.53-1.72 (m, 16H), 1.79-2.06 (m, 12H), 2.13 (d, 3H), 3.92 (s, 2H),4.18 (m, 2H), 6.98 (m, 1H), 7.16 (m, 2H), 7.42-7.98 (br, 1H).

Example 86N-(2-Adamantyl)-2-methylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following procedures analogous to thosedescribed in Example 87 using2-methylspiro[isoindoline-1,4′-piperidine]-3-thione in place ofspiro[isoindoline-1,4′-piperidine]-3-thione in Step 1. LC-MS Method 1t_(R)=1.26 min, m/z=380; ¹H NMR (CD₃OD) δ=7.68 (m, 1H), 7.47 (m, 3H),3.00 (s, 3H), 2.26 (m, 2H), 1.64 (d, 2H).

Example 87N-(2-Adamantyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide

Step 1

Crude spiro[isoindoline-1,4′-piperidine]-3-thione TFA salt was taken upin 1:1 MeCN:10% aq K₂CO₃ (10 mL) and 2-adamantylisocyanate (52 mg, 0.30mmol, 2.5 equiv) was added. After 2 h the desired thiolactam, urea wasformed. The mixture was concentrated to ˜50% of its original volume anddiluted with EtOAc. The mixture was washed with 1.0 M aq HCl and brine,dried over Na₂SO₄, and evaporated. The residue was purified by flashchromatography on silica (4 g), eluting with 20-80% EtOAc in hexanes,affordingN-(2-adamantyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(51 mg, 0.093 mmol, 85% yield) as a pale yellow solid.

Step 2

N-(2-adamantyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(6 mg, 0.015 mg, 1.0 equiv) and Raney Nickel (˜100 mg) were heated at60° C. in ethanol (10 mL) for 0.5 h. After this time LC-MS showedcomplete reduction of the thiolactam. The mixture was cooled to rt,filtered and evaporated. The residue was purified by prep HPLC to affordN-(2-adamantyl)spiro[isoindoline-1,4′-piperidine]-1′-carboxamide as itsTFA salt. LC-MS Method 1 t_(R)=1.28 min, m/z=366; ¹H NMR (CD₃OD) δ=7.45(m, 3H), 4.14 (m, 2H), 2.20 (m, 2H), 1.64 (d, 2H).

Example 887-Chloro-N-(2-adamantyl)-2-methylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide

Step 1

7-Chloro-2-methylspiro[isoindoline-1,4′-piperidine]-3-thione TFA salt(0.628 mmol, 1.0 equiv) was dissolved in 1:1 AcCN:10% aq K₂CO₃ (10 mL).To this solution 2-adamantyl isocyanate (140 mg, 0.786 mmol, 1.25 equiv)was added and the mixture stirred for 2 h. After this time the desiredurea was formed. The mixture was concentrated to ˜50% of its originalvolume and diluted with EtOAC. The mixture was washed with 1.0 M aq HCland brine, dried over Na₂SO₄, and evaporated. The residue was purifiedby flash chromatography on silica (12 g), eluting with 20-80% EtOAc inhexanes, affording7-chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(217 mg, 78% yield) as a pale yellow solid.

Step 2

7-Chloro-N-(2-adamantyl)-2-methyl-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(21 mg, 0.038 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ (5 mL) and thesolution was cooled to 0° C. Methyl triflate (145 mg, 100 μL, 0.84 mmol,23 equiv) was added and the methylation of the thiolactam, monitored byLC-MS. To this solution was added NaBH₄ (100 mg, 2.6 mmol, ˜70 equiv)and the mixture allowed to stir for 0.5 h. After this, time LC-MS showedformation of the desired amine. The mixture was diluted with CH₂Cl₂ (˜10mL) and quenched by addition of satd aq NH₄Cl. The layers were separatedand the organic layer was dried over Na₂SO₄, and evaporated. The residuewas purified by preparative HPLC to afford7-Chloro-N-(2-adamantyl)-2-methylspiro[isoindoline-1,4′-piperidine]-1′-carboxamideas its TFA salt. LC-MS Method 1 t_(R)=1.35 min, m/z=414; ¹H NMR (CD₃OD)δ=7.4 (m, 3H), 3.87 (m, 1H), 3.11 (s, 3H),

Example 892-(1′-((1-(Benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid

The title compound was prepared following procedures analogous to thosedescribed in Example 72 using benzylamine in Step 1. LC-MS Method 5t_(R)=1.317 min, m/Z=557.1; ¹H NMR (CDCl₃) δ=1.23-1.61 (m, 7H), 1.67 (m.2H), 1.76-2.03 (m, 9H), 2.18 (m, 4H), 2.29-2.61 (m, 9H), 2.61-2.93 (m,3H), 3.06 (m, 1H), 3.48 (s, 2H), 3.97 (m, 2H), 4.23-4.45 (m, 2H), 4.73(m, 1H), 6.05-6.26 (d, 2H), 7.02 (m, 3H), 7.06-7.29 (m, 4H), 7.34 (m,2H).

Example 904-(1′-(2-Adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-4-oxobutanoicacid

To a solution ofN-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (20 mg,0.06 mmol) and succinic anhydride (12 mg, 0.12 mmol) in CH₂Cl₂ (5 mL)was added TEA. After stirred for 2 h at rt the solvent was removed togive4-(1′-(2-adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-4-oxobutanoicacid (20 mg, 74%). LC-MS Method 5 t_(R)=3.6 min, m/z=953.1; ¹H NMR(CD₃OD) δ=1.69 (d, 2H), 1.75 (d, 2H), 1.80-1.99 (m, 11H), 2.00-2.10 (m,5H), 2.20 (s, 2H), 2.60-2.70 (m, 2H), 2.80-2.90 (m, 2H), 3.06-3.18 (m,2H), 3.93 (s, 1H), 4.10-4.19 (m, 2H), 4.20 (s, 2H), 5.90 (d, 1H), 7.10(m, 1H), 7.19-7.28 (m, 2H), 8.16 (d, 1H).

Example 91 (E)-4-(1′-(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-4-oxobut-2-enoicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamideand maleic anhydride following a procedure analogous to that describedin Example 90. LC-MS Method 1 t_(R)=1.7 min, m/z=478; ¹H NMR (CDCl₃)1.60-2.20 (18H), 3.11 (m, 2H), 3.58 (s, 2H), 3.92 (br s, 4H), 4.39 (s,2H), 5.00 (br s, 1H), 6.30-7.45 (6H).

Example 924-(1′-(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-4-oxobutanoicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamidefollowing a procedure analogous to that described in Example 90. LC-MSMethod 5 t_(R)=2.055 min, m/z=480.2; ¹H NMR (CD₃OD) δ=1.56-1.70 (m, 4H),1.74-1.88 (m, 8H), 1.84-2.08 (m, 6H), 2.65 (m, 2H), 2.76 (m, 2H),3.15-3.24 (m, 2H), 3.84 (m, 2H), 3.92 (s, 2H), 4.01 (m, 1H), 7.16-7.29(m, 3H), 7.41 (m, 1H):

Example 935-(1′-(2-Adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-5-oxopentanoicacid

The title compound was prepared from glutaric anhydride following aprocedure analogous to that described in Example 90. LC-MS Method 4t_(R)=2.341 min, m/z=480.3; ¹H NMR (CDCl₃) δ=1.62 (m, 4H), 1.69 (m, 6H),1.79 (m, 6H), 1.88 (m, 3H), 2.05 (m, 4H), 2.51 (m, 4H), 2.95 (m, 2H),3.87 (m, 1H), 3.91 (m, 2H), 3.94 (m, 1H), 7.02 (m, 1H), 7.09 (m, 1H),7.19 (m, 1H), 7.24 (m, 1H), 8.16 (m, 1H).

Example 944-(1′-(2-Adamantyloxycarbonyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-4-oxobutanoicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamidefollowing a procedure analogous to that described in Example 90. LC-MSMethod 1 t_(R)=1.95 min, m/z=480; ¹H NMR (CD₃OD) δ=7.38 (m, 1H),7.26-7.13 (m, 3H), 4.81 (s, 2H), 4.09 (m, 2H), 3.85 (m, 1H), 3.23 (m,1H), 2.77 (m, 2H), 2.65 (m, 2H).

Example 955-(1′(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-5-oxopentanoicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamideand glutaric anhydride following a procedure analogous to that describedin Example 90. LC-MS Method 5 tR=2.034 min, m/z=494.3; ¹H NMR (CD₃OD)δ=1.52-1.69 (m, 4H), 1.79-2.04 (m, 16H), 2.41 (m, 2H), 2.62 (m, 2H),3.16-3.27 (m, 2H), 3.86 (m, 2H), 3.98 (m, 3H), 7.15-7.39 (m, 3H), 7.41(d, 1H).

Example 965-(1′-(2-Adamantylcarbamoyl)spiro[indoline-3,4′-piperidine]-1-yl)-3,3-dimethyl-5-oxopentanoic acid

The title compound was prepared from 3,3-dimethylglutaric anhydridefollowing a procedure analogous to that described in Example 90. LC-MSMethod 4 t_(R)=2.815 min, m/z=508.3; ¹H NMR (CDCl₃) δ=1.18 (s, 6H), 1.64(m, 6H), 1.73 (m, 8H), 1.86 (m, 8H), 1.95 (m, 10H), 2.55 (s, 2H), 2.66(s, 2H), 3.01 (m, 2H), 4.00 (m, 2H), 4.05 (s, 3H), 4:92 (s, 1H), 7.19(m, 2H), 7.31 (m, 2H), 8.29 (m, 1H):

Example 974-(1′-(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-2,2-dimethyl-4-oxobutanoicacid

A vial was charged with 3,3-dimethylsuccinic anhydride (7.4 mg, 58μmol), DIEA (15 mL, 90 μmol) and CH₂Cl₂ (1 mL). A solution ofN-(2-adamantyl)-2,3-dihydro-1,4-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide(25 mg, 53 μmol) in CH₂Cl₂ (1 mL) was added and the mixture was stirredovernight. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL)and allowed to stand for 5 min. The reaction mixture was applied to thecartridge and eluted with ether (20 mL). The eluate was evaporated todryness and the residue was purified by preparative HPLC to afford4-(1′-(2-adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-2,2-dimethyl-4-oxobutanoicacid (17 mg, 63%). LC-MS Method 1 t_(R)=1.87 min, m/z=508; ¹H NMR(CDCl₃) 1.32 (s, 6H), 1.50-2.10 (18H), 2.73 (s, 2H), 3.20 (m, 2H), 3.90(m, 4H), 3.94 (s, 1H), 4.70 (s, 2H), 4.98 (1H), 7.05-7.40 (4H).

Example 985-(1′-(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)-3,3-dimethyl-5-oxopentanoicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1,1-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamideand 3,3-dimethylglutaric anhydride following a procedure analogous tothat described in Example 99. LC-MS Method 5 t_(R)=2.508 min, m/z=522.3;¹H NMR (CD₃OD) δ=1.10-1.20 (m, 6H), 1.53-1.70 (m. 4H), 1.77-1.90 (m,8H), 1.90-2.06 (m, 6H), 2.40-2.50 (m, 2H), 2.64-2.72 (m, 2H), 3.21 (m,1H), 3.89 (s, 1H), 3.91-4.04 (m, 3H), 7.13-7.29 (m, 3H), 7.40 (d, 1H).

Example 99(1S,2R)-2-(1′42-Adamantylcarbamoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-2-ylcarbonyl)cyclopropanecaxboxylicacid

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamideand 3-oxabicyclo[3.1.0]hexane-2,4-dione following a procedure analogousto that described in Example 99. LC-MS Method 1 tR=1.7 min, m/z=492;¹HNMR (CDCl₃) δ=1.45-2.35 (21H), 3.09 (m, 2H), 3.77 (d, 1H), 3.82 (d,1H), 3.94 (s, 2H), 4.10 (d, 1H), 4.79 (m, 1H), 4.88 (s, 2H), 4.96 (1H),7.05-7.40 (4H).

Example 100(1RS,2RS)-2-(1′-(2-Adamantyloxycarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-2-ylcarbonyl)cyclopropanecarboxylicacid

Step 1

2-Adamantyl2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate (12mg, 0.025 mmol), trans-2-(ethoxycarbonyl)cyclopropanecarboxylic acid (8mg, 2.5 equiv), HATU (11 mg, 1.15 equiv), DIEA (13 μL, 3 equiv) weremixed with CH₂Cl₂ (2 mL) and put on shaker for 1 h at rt. The mixturewas diluted with EtOAc (8 mL), washed with 3% aq HCl (2×3 mL),concentrated and purified by preparative HPLC to afford 2-adamantyl2-((1R,2R)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate(9 mg, 69%).

Step 2

2-Adamantyl2-((1RS,2RS)-2-(ethoxycarbonyl)cyclopropanecarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate(9 mg, 0.017 mmol) was mixed with 2N aq LiOH (2004, excess) andacetonitrile (3 mL). The mixture was stirred overnight at rt. LC-MSshowed the reaction was complete. The mixture was concentrated,acidified with 5% aq HCl and extracted with EtOAc (3×3 mL). The combinedorganic layers were concentrated and purified by preparative HPLC toafford(1RS,2RS)-2-(1′-(2-adamantyloxycarbonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-2-ylcarbonyl)cyclopropanecarboxylic acid (4.6 mg,54%). LC-MS Method 1 t_(R)=1.98 min, m/z=493; ¹H NMR (CDCl₃) δ=7.37 (t,1H), 7.31-7.19 (m, 2H), 7.13 (d, 1H), 4.89 (m, 3H), 4.16 (m, 3H), 3.15(m, 2H), 2.50 (m, 1H), 2.29 (m, 1H).

Example 101.1 Ethyl2-(7-bromo-1′-(2-adamantylcarbamoyl)spiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate

To a solution of 2-aminoadamantane hydrochloride (4.17 g, 22 mmol) andDIEA (28.7 g, 223 mmol) in anhydrous CH₂Cl₂ (40 mL) was added CDI (4.33g, 27 mmol) at 0° C. and then stirred for 1 h at 0° C. under N₂atmosphere. Ethyl2-(7-bromospiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate (7.77 g,22 mmol) in CH₂Cl₂ anhydrous (40 mL) was added dropwise to the abovemixture. The mixture was stirred for 8 h at rt under N₂. The reactionmixture was washed with 1 N aq HCl. The organic layer was dried overNa₂SO₄, filtered and concentrated to leave a residue, which was purifiedby silica gel column chromatography to afford ethyl2-(7-bromo-1′-(2-adamantylcarbamoyl)spiro[indene-1,4′-piperidine]-3(2H)-ylidene)acetate(4.1 g, 35%). Preparative SFC using a ChiralCel-OJ, 400×25 mm I.D, 20 μm(Daicel Chemical Industries, Ltd) column maintained at 35° C. elutedwith 75:25 supercritical CO₂/MeOH at a flow rate of 70 mL min⁻¹ and anozzle pressure of 100 bar afforded two isomers.

Isomer 1: LC-MS Method 5 t_(R)=1.799 min, m/z=529; ¹H NMR (CDCl₃)δ=1.22-1.29 (t, 3H), 1.51-1.70 (m, 10H), 1.71-1.81 (m, 4H), 1.82-1.91(m, 7H), 1.92-2.03 (m, 2H), 2.95-3.21 (m, 4H), 3.53 (m, 2H), 3.98-4.15(m, 3H), 4.15-4.24 (m, 2H), 4.98 (br, 1H), 6.91 (s, 1H), 7.02-7.08 (m,1H), 7.20-7.26 (m, 1H), 7.32-7.36 (m, 1H).

Isomer 2: LC-MS Method 5 t_(R)=1.9 min, m/z=529.1; ¹H NMR (CDCl₃)δ=1.30-1.38 (m, 4H), 1.51-1.70 (m, 8H), 1.70-1.81 (m, 4H), 1.83-1.89 (m,6H), 1.92-2.01 (m, 2H), 2.78-2.97 (m, 2H), 3.02-3.17 (m, 2H), 3.32 (s,2H), 3.96-4.08 (m, 3H), 4.20-4.29 (m, 2H), 4.89-5.01 (br, 1H), 6.33 (s,1H), 7.12-7.20 (t, 1H), 7.52-7.60 (m, 2H).

Example 1023-Allyl-7-chloro-N-(2-adamantyl)-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide

Step 1.

A solution of tert-butyl7-chloro-3-hydroxy-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxylate(0.0175 g, 0.0514 mmol, 1.0 equiv) and allyltrimethylsilane (0.1660 g,1.45 mmol, 28 equiv) in CH₂Cl₂ (2 mL) was cooled to −78° C. Borontrifluoride diethyl etherate was added dropwise (10 drops, 0.0520 g, 7.1equiv), and the solution was allowed to stir, coming to ambienttemperature, for 16 h. The reaction was then quenched with 1 mL of satdaq K₂CO₃, diluted with CH₂Cl₂, and dried over K₂CO₃. After the solventswere evaporated, the crude3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine] (0.0190 g) wasdirectly used in the next step without further purification. LC-MSMethod 1 t_(R)=1.18 min, m/z 266, 264 (MO. Step 2

To a stirred solution of3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine] (0.0190 g), andDIEA (0.5 mL) in CH₂Cl₂ (2 mL) was added 2-adamantyl isocyanate (0.0138g, 0.0778 mmol) at rt. After 19 h, the solvents were removed in vacuoand the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μC18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH₃CN/H₂O, 0.1% CF₃COOHover 8 min and then 90% CH₃CN/H₂O, 0.1% CF₃COOH over 4 min, flow rate 25mL/min) to affordN-(2-adamantyl)-3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide(0.0220 g, 97%). LC-MS Method 1 t_(R)=2.33 min, m/z 443, 441 (MH⁺); ¹HNMR (400 MHz, CDCl₃) δ=7.24-7.20 (m, 2H), 7.09-7.05 (m, 1H), 5.87-5.77(m, 1H), 5.25 (t, J=5.7 Hz, 1H), 5.15-5.08 (m, 2H), 3.98 (br s, 1H),3.94-3.88 (m, 2H), 136-3.28 (m, 2H), 2.66-2.38 (m, 4H), 1.95-1.25 (m,16H).

Example 103N-(2-Adamantyl)-2,3,3-trimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from2-methylspiro[isoindoline-1,4′-piperidine]-3-thione following proceduresanalogous to those described in Example 104 Steps 1 and 2. LC-MS Method1 t_(R)=1.33 min, m/z=408; ¹H NMR (CD₃OD) δ=7.81 (d, J=7.4, 1H), 7.50(m, 3H), 3.00 (s, 3H), 2.37 (m, 2H), 1.64 (d, 2H).

Example 1047-Chloro-N-(2-adamantyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide

Step 1

To a solution of crude7-chloro-2-(4-methoxybenzyl)spiro[isoindoline-1,4′-piperidine]-3-thioneTFA salt (prepared from TFA deprotection of tert-butyl7-chloro-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxylate(52 mg, 0.11 mmol)) in 1:1 MeCN:10% aq K₂CO₃ (10 mL), was added2-adamantylisocyanate (50 mg, 0.30 mmol, 2.6 equiv) and the mixturestirred was for 2 h. After this time LC-MS analysis showed formation ofthe desired urea. The mixture was concentrated to ˜50% of its originalvolume and diluted with EtOAc. The mixture was washed with 1.0 M aq HCland brine, dried over Na₂SO₄, and evaporated. The residue was purifiedby flash chromatography on silica gel (4 g), eluting with 20-80% EtOAcin hexanes, affording7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(51 mg, 0.093 mmol, 85% yield) of the desired thiolactam-urea as a paleyellow solid.

Step 2

7-Chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3-thioxospiro[isoindoline-1,4′-piperidine]-1′-carboxamide(˜10 mg, ˜0.018 mmol, 1.0 equiv) was dissolved in CH₂Cl₂ (5 mL) and thesolution cooled to 0° C. Methyl triflate (9 mg, 6 μL, 0.054 mmol, 3.0equiv) was added and the methylation of the thiolactam was monitored byLC/MS. To this solution was added MeMgBr (3.0 M in THF, 10 equiv, 6 μL)and the mixture allowed to stir for 0.5 h. After this time LC-MS showedformation of the desired amine. The mixture was diluted with CH₂Cl₂ (˜10mL) and quenched by addition of satd aq NH₄Cl. The layers were separatedand the organic layer was dried over Na₂SO₄, and evaporated to affordcrude7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamidewhich was used without further purification.

Step 3

Crude7-chloro-N-(2-adamantyl)-2-(4-methoxybenzyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamidewas dissolved in neat TFA (3 mL) and the mixture was heated to 80° C.for 17 h. After this time LC-MS analysis showed complete removal of thep-methoxybenzyl group. The solution was evaporated the amine purified byprep HPLC to afford7-chloro-N-(2-adamantyl)-3,3-dimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamideas its TFA salt. LC-MS Method 1 t_(R)=1.43 min, m/z=428; ¹H NMR (CD₃OD)δ=7.47 (m, 2H), 7.37 (m, 1H), 4.22 (m, 2H), 3.89 (s, 1H), 3.21 (t,J=12.9, 2H).

Example 1057-Chloro-N-(2-adamantyl)-2,3,3-trimethylspiro[isoindoline-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from7-chloro-2-methylspiro[isoindoline-1,4′-piperidine]-3-thione followingprocedures analogous to those described in Example 104 Steps 1 and 2.LC-MS Method 1 t_(R)=1.42 min, m/z=442; ¹H NMR (CD₃OD) δ=7.51 (m, 2H),7.42 (m, 1H), 3.88 (m, 1H), 3.53 (m, 2H), 3.26 (s, 3H).

Example 106

Methyl 3-(1′-(2-adamantylcarbamoyl)-1-H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-ylsulfonyl)propanoate

The title compound was prepared following a procedure analogous to thatdescribed in Example 34 using methyl 3-(chlorosulfonyl)propionate inplace of MeSO₂Cl. LC-MS Method 1 t_(R)=1.94 min, m/z=530; ¹H NMR (CDCl₃)δ=1.60-2.15 (18H), 2.90 (t, 2H), 3.13 (m, 2H), 3.39 (t, 2H), 3.57 (s,2H), 3.75 (s, 3H), 3.90 (d, 2H), 3.99 (br s, 1H), 4.49 (s, 2H), 4.86 (brs, 1H), 7.05-7.40 (4H).

Example 107 2-Adamantyl2-(3-methoxy-3-oxopropylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxylate

The title compound was prepared following a procedure analogous to thatdescribed in Example 34 using methyl 3-(chlorosulfonyl)propanoate inplace of methanesulfonyl chloride. LC-MS Method 1 t_(R)=2.22 min,m/z=531; ¹H NMR (CDCl₃) δ=7.36 (d, 1H), 7.27 (t, 1H), 7.21 (t, 1H), 7.07(d, 1H), 4.87 (s, 1H), 4.50 (br s, 2H), 4.30 (br s, 2H), 4.18 (d, 2H),3.73 (s, 3H), 3.37 (t, 2H), 3.10 (br s, 2H), 2.90 (t, 2H).

Example 1083-(1′-(2-Adamantylcarbamoyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-ylsulfonyl)propanoicacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 6. LC-MS Method 1 t_(R)=1.83 min, m/z=516; ¹H NMR(CDCl₃) δ=1.60-2.15 (18H), 2.93 (t, 2H), 3.15 (m, 2H), 3.42 (t, 2H),3.57 (s, 2H), 3.90 (d, 2H), 3.97 (br s, 1H), 4.52 (s, 2H), 7.00-7.40(4H).

Example 1093-(1′-(2-Adamantyloxycarbonyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-ylsulfonyl)propanoicacid

The title compound was prepared following a procedure analogous to thatdescribed in Example 6. LC-MS Method 1 tR=2.02 min, m/z=516; ¹HNMR(CDCl₃) δ=7.36 (d, 1H), 7.26 (t, 1H), 7.20 (t, 1H), 7.06 (d, 1H), 4.87(s, 1H), 4.49 (br d, 2H), 4.17 (d, 2H), 3.74 (br s, 1H), 3.37 (t; 2H),3.07 (br d, 1H), 2.94 (t, 2H).

Example 1107-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(piperazin-1-yl)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

Step 1.

A DMF (0.2 mL) solution of 1-Boc-piperazine (2.5 mg, 0.013 mmol),carboxylic acid (6 mg, 0.012 mmol), HATU (5.7 mg, 0.015 mmol), andi-Pr₂NEt (1 drop) was prepared and allowed to stir for several hours.The solution was diluted with CH₃CN (0.3 mL) and purified by preparativeHPLC to afford tert-butyl4-(2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetyl)piperazine-1-carboxylate(6 mg).

Step 2.

tert-Butyl4-(2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]:3-yl)acetyl)piperazine-1-carboxylate(6 mg) was dissolved in CH₂Cl₂ (1 mL) and treated with 20% TFA for 30min. The solvent was evaporated and the crude material purified bypreparative HPLC to afford(±)-7-bromo-N-(2-adamantyl)-3-(2-oxo-2-(piperazin-1-yl)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(1.83 mg). LC-MS Method 1 t_(R)=1.51 min, m/z=569 (M+1); ¹H NMR (CD₃OD)δ=7.37 (d, 1H), 7.24 (d, 1H), 7.09 m (t, 1H), 4.09-4.04 (m, 2H),3.66-3.62 (m, 1H), 2.97 (t, 1H), 2.76 (dd, 1H), 2.61 (dd, 1H), 2.45 (dt,1H), 1.43 (m, 2H).

Example 1117-Bromo-N-(2-adamantyl)-3-(2-morpholino-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using morpholine in place of 1-Boc-piperazine. LC-MS Method 1t_(R)=1.98 min, m/z=570 (M+1); ¹H NMR (CDCl₃) δ=7.38 (d, 1H), 7.12 (d,1H), 7.06 (t, 1H), 4.95 (br s, 1H), 4.4-3.98 (m, 2H), 3.89 (dd, 1H),3.72 (3.67 (m, 7H), 3.48 (m, 2H), 3.15-3.06 (m, 2H), 2.99 (dt, 1H), 2.88(dd, 1H), 2.75 (dd, 1H), 2.51-2.42 (m, 2H), 1.94 (br s, 2H), 1.85 (br s,6H), 1.79-1.57 (m, 7H), 1.422 (ddd, 2H).

Example 1127-Bromo-N-(2-adamantyl)-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using 1-methylpiperazine in place of 1-Boc-piperazine. LC-MSMethod 1 t_(R)=1.52 min, m/z=583 (M+1); ¹H NMR (CD₃OD) δ=7.37 (d, 1H),7.23 (d, 1H), 7.09 (t, 1H), 4.72 (br s, 1H), 4.24 (br s, 1H), 4.06 (m,2H), 3.87 (s, 1H), 3.66-3.48 (m, 4H), 3.16-3.04 (m, 5H), 2.94 (s, 3H),2.77 (dd, 1H), 2.62 (dd, 1H), 2.45 (dt, 1H), 2.03-1.79 (m, 12H),1.70-1.61 (m, 3H), 1.40 (t, 2H).

Example 113N-(2-Adamantyl)-2-(4-(dimethylamino)butanoyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide

The title compound was prepared fromN-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamideand 4-(dimethylamino)butanoic acid following the procedure of Example110 Step 1. LC-MS Method 1 t_(R)=2.4 min, m/z=493.38; ¹HNMR (CD₃OD)δ=1.55-1.73 (m, 4H), 1.80-1.94 (m, 8H), 1.95-2.10 (m, 8H), 2.66-2.72 (m,2H), 2.82-2.92 (s, 6H), 3.05-3.19 (m, 2H), 3.19-3.28 (m, 2H), 3.80-3.92(m, 1H), 3.92 (s, 3H), 3.93-4.04 (m, 1H), 4.72-4.80 (m, 2H), 5.78-5.95(m, 1H), 7.15-7.30 (m, 3H), 7.40-7.47 (m, 1H).

Example 1147-Bromo-N-(2-adamantyl)-3-(2-(2-(dimethylamino)ethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using N,N-dimethylethylenediamine in place of 1-Boc-piperazine.LC-MS Method 1 t_(R)=1.51 min, m/z=571 (M+); ¹H NMR (CD₃OD) δ 7:38 (d,114), 7.19 (d, 1H), 7.10 (t, 1H), 4.06 (t, 3H), 2.96 (s, 6H), 283 (dd,2H), 2.65 (dd, 2H), 2.48 (m, 2H), 2.37 (dd, 2H), 1.62 (d, 3H), 1.39 (d,3H).

Example 1157-Bromo-N-(2-adamantyl)-3-(2-(methyl(2-(methylamino)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using N,N′-dimethylethylenediamine in place of 1-Boc-piperazine.LC-MS Method 1 t_(R)=1.53 min, m/z=571 (M+); ¹H NMR (CD₃OD) δ=7.37 (d,1H), 7.23 (d, 1H), 7.09 (t, 1H), 4.07 (d, 2H), 3.87 (br s, 1H), 3.22 (t,2H), 3.10 (s, 3H), 2.75 (s, 3H), 2.59 (dd, 1H), 2.45 (dd, 1H), 1.40 (m,2H).

Using a procedure analogous to that described in Example 110 Step1,2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid, isomer 1 was converted into7-bromo-N-(2-adamantyl)-3-(2-(methyl(2-(methylamino)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide,isomer 1. LC-MS Method 5 t_(R)=1.136 min, m/z=571.1; ¹H NMR (CDCl₃)δ=1:34 (m, 2H), 1.52 (m. 1H), 1.60 (m, 2H), 1.65 (m, 3H), 1.78 (m, 6H),1.86 (m, 2H), 2.26 (m, 7H), 2.42 (m, 2H), 2.62 (m, 1H), 2.70 (m, 2H),2.89 (m, 2H), 3.02 (m, 4H), 3.23 (m, 1H), 3.46-3.72 (m, 3H), 3.90 (m,3H), 4.86 (s, 1H), 7.03 (m, 2H), 7.31 (m, 1H).

Using a procedure analogous to that described in Example 110 Step 1,2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid,isomer 2 was converted into7-bromo-N-(2-adamantyl)-3-(2-(methyl(2-(methylamino)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide,isomer 2. LC-MS Method 5 tR=1.138 min, m/z=571.1; 1H NMR (CDCl₃) δ=1.41(m, 2H), 1.65 (m, 2H), 1.71-1.79 (m, 8H), 1.92 (m, 2H), 2.19 (m, 6H),2.33-2.68 (m, 2H), 2.79 (m, 4H), 3.01 (m, 5H), 3.32 (m, 1H), 3.41 (m,1H), 3.71 (m, 2H), 3.99 (m, 2H), 4.11-4.23 (m, 1H), 7.11 (m, 2H), 7.42(m, 1H), 9.51-9.72 (br, 1H).

Example 1167-Bromo-N-(2-adamantyl)-3-(24(2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using N,N,N′-trimethylethylenediamine in place of1-Boc-piperazine. LC-MS Method 1 t_(R)=1.55 min, m/z=585 (M+1); ¹H NMR(CD₃OD) δ=7.37 (d, 1H), 7.23 (d, 1H), 7.09 (t, 1H), 4.07 (d, 2H), 3.87(s, 1H), 3.85-3.74 (m, 2H), 3.65-3.62 (m, 1H), 3.35 (t, 2H), 3.11 (s,3H), 2.99 (s, 3H), 2.78 (dd, 1H), 2.59 (dd, 1H), 2.44 (dt, 1H),1.42-1.38 (m, 2H).

Example 1177-Bromo-N-(2-adamantyl)-3-(2-(3-(dimethylamino)propylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using N,N-dimethylpropylenediamine in place of 1-Boc-piperazine.LC-MS Method 1 t_(R)=1.51 min, m/z=585 (M+); ¹H NMR (CD₃OD) δ=7.37 (d,1H), 7.19 (d, 1H), 7.09 (t, 1H), 4.07 (t, 2H), 3.87 (s, 1H), 3.60 (m,1H), 3.16 (dd, 2H), 288 (s, 6H), 2.76 (dd, 1H), 2.61 (dd, 1H), 2.49 (dt,1H), 2.3 (dd, 1H), 1.39 (d, 2H).

Example 1187-Bromo-N-(2-adamantyl)-3-(2-(4-(dimethylamino)butylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4-r-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using N,N-dimethylbutylenediamine in place of 1-Boc-piperazine.LC-MS Method 1 t_(R)=1.52 min, m/z=599 (M+).

Example 1197-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(2-(piperazin-1-yl)ethylamino)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110using tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate in place of1-Boc-piperazine. LC-MS Method 1 t_(R)=1.41 min, m/z=614 (M⁺); ¹H NMR(CD₃OD) δ=7.38 (d, 1H), 7.22 (d, 114), 7.10 (t, 1H), 4.07 (m, 2H), 3.87(m, 1H), 2.90 (dd, 1H), 2.66 (dd, 1H), 2.48 (jm, 1H), 2.42 (dd, 1H).

Example 1207-Bromo-N-(2-adamantyl)-3-(2-(2-morpholinoethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using 2-morpholinoethanamine in place of 1-Boc-piperazine. LC-MSMethod 1 t_(R)=1.52 min, m/z=613 (M+); ¹H NMR (CD₃OD) δ=7.38, 7.20,7.10, 4.07, 2.83, 2.65, 2.48, 2.38, 1.63, 1.39.

Example 1217-Bromo-N-(2-adamantyl)-3-(2-(2-(4-methylpiperazin-1-yl)ethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared following the procedure of Example 110Step 1 using 2-(4-methylpiperazin-1-yl)ethanamine in place of1-Boc-piperazine. LC-MS Method 1 t_(R)=1.45 min, m/z=626 (M⁺); ¹H NMR(CD₃OD) δ=7.38 (d, 1H), 7.21 (d, 1H), 7.10 (t, 1H), 4.07 (m, 3H), 3.87(s, 1H), 3.62 (m, 2H), 2.88 (s, 3H), 2.77 (dd, 2H), 2.70 (t, 2H), 2.62(dd, 2H), 2.49 (m, 2H), 2.34 (dd, 2H), 1.63 (d, 2H), 1.40 (d, 2H).

Example 122(±)-7-Bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

To a solution of (±)-ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate(300 mg, 0.566 mmol) in THF (5 mL) was added LiAlH₄ (65 mg, 1.132 mmol)at 0° C. under N₂. The mixture was stirred overnight at rt. The mixturewas separated by preparative TLC to give the crude product, which waspurified by preparative HPLC to afford(±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(26 mg, 10%). LC-MS Method 5 t_(R)=1.467 min, m/z=489.1; ¹H NMR: (400MHz, CDCl₃): δ=1.38 (m, 2H), 1.62 (m. 5H), 1.71 (m, 5H), 1.75-1.88 (m,9H), 2.19 (m, 2H), 2.21-2.49 (m, 5H), 2.52 (m, 1H), 2.95-3.12 (m, 3H),3.21 (m, 1H), 3.78 (m, 2H), 3.82 (m, 3H), 7.03 (m, 1H), 7.08 (m, 1H),7.32 (m, 1H).

Example 123(±)-7-Bromo-N-(2-adamantyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

To a solution of (±)-ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropandate(18 mg, 0.0323 mmol) in dry CH₂Cl₂ was added DIBAL (0.15 mL, 3 eq) at−78° C. The mixture was stirred for 30 min and quenched with methanol.The organic layer was separated, dried and concentrated to give(±)-7-bromo-N-(2-adamantyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide.LC-MS Method 5 t_(R)=1.574 min, m/z=517.1; ¹H NMR: (400 MHz, CDCl₃):δ=0.89 (s, 3H), 0.98 (s, 3H), 1.22 (m, 2H), 1.40 (m, 2H), 1.54 (m, 7H),1.77 (m, 11H), 1.89 (m, 2H), 2.34 (m, 2H), 3.02 (m, 3H), 3.31 (m, 1H),3.52 (m, 2H), 3.90 (m, 3H), 6.96 (m, 1H) 7.28 (m, 2H).

Example 124 (±)-2-Adamantyl3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

A 100-mL of flask was charged with(±)-2-(7-bromo-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid (30 mg, 0.06 mmol) dissolved in THF (3 mL) and treated with TEA (2mL). Then diphenylphosphoryl azide (18 mg, 0.066 mmol) was addeddropwise slowly. The mixture was stirred for 3 h at rt. 1 N aq NaOHsolution (3 mL) was added and the reaction mixture was reflux overnight.The solvent was removed in vacuo and the aqueous residue was extractedwith CH₂Cl₂ (3×5 mL). The organic layers were combined, washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by preparative HPLC to give (±)-2-adamantyl3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(1 mg, 4%). LC-MS Method 5 t_(R)=1.175 min, m/z=475; ¹H NMR (400 MHz,MeOD): δ=0.71-0.83 (m, 3H), 1.46-1.57 (m. 2H), 1.61-1.81 (m, 6H),1.81-2.06 (m, 11H), 2.39-2.51 (m, 1H), 2.83-3.00 (m, 2H), 3.41-3.57 (m,2H), 4.07-4.14 (m, 1H), 4.79 (m, 1H), 6.99-7.10 (m, 2H), 7.37 (m, 1H),7.95-8.30 (s, 1H).

Example 125 (±)-2-Adamantyl7-bromo-3-((dimethylamino)methyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate

A 50-mL flask was charged with (±)-2-adamantyl3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(60 mg, 0.12 mmol), CH₂O (16 mg, 0.53 mmol) and HCOOH (33 mg, 0.72mmol). The mixture was stirred overnight under reflux. 6 N aq HCl (3 mL)was added and the mixture was extracted with CH₂Cl₂ (3×5 mL). Theaqueous layer was basified with 1 N aq NaOH (10 mL) and extracted withCH₂Cl₂ (3×5 mL). The organic layers were combined, washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude residue waspurified by preparative HPLC to give (±)-2-adamantyl7-bromo-3-((dimethylamino)methyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate(10 mg, 9%). LC-MS Method 5 t_(R)=1.229 min, =503.1; ¹H NMR (400 MHz,MeOD): δ=1.44 (m, 2H), 1.66 (d, 2H), 1.72-1.90 (m, 8H), 1.94 (m, 2H),1.98-2.10 (m, 4H), 2.38-2.50 (br, 1H), 2.79 (m, 1H), 3.01 (m, 6H), 3.11(m, 2H), 3.71 (m, 2H), 4.15-4.30 (m, 2H), 7.07 (m, 1H), 7.29 (d, 1H),7.45 (d, 1H).

Example 126(±)-7-Bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

Step 1

To a solution of(±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(40 mg, 0.082 mmol) and Et₃N (9.9 mg, 0.098 mmol) in dry CH₂Cl₂(5 mL)was added TsCl (15.6 mg, 0.082 mmol) at 0° C. The mixture was stirredovernight at rt. The mixture was concentrated to give the crude product,which was purified by preparative TLC to give(±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(50 mg, crude).

Step 2

To a solution of(±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(50 mg, 0.078 mmol) and K₂CO₃ (21.56 mg, 0.156 mmol) in anhydrous CH₃CN(3 mL) was added NaI (3 mg, 0.020 mmol) at 0° C. Then the mixture wasstirred overnight at 80-90° C. The mixture was concentrated to give thecrude product which was purified by preparative HPLC to afford(±)-7-bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(4 mg, 9%). LC-MS Method 5 t_(R)=1.09 min, m/z=558; ¹H NMR: (400 MHz,CDCl₃): δ=1.43 (m, 2H), 1.56-1.69 (m. 3H), 1.75-1.85 (m, 9H), 1.94-2.05(m, 3H), 2.45-2.59 (m, 4H), 2.91 (m, 2H), 3.12 (m, 5H), 3.25 (m, 2H),3.56 (m, 3H), 3.91-4.16 (m, 6H), 4.20 (m, 2H), 7.12 (m, 2H), 7.40 (m,1H).

Example 127 (±)-3-(2-Amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

To a solution of the compound 1 (200 mg, 0.47 mmol) in CH₂Cl₂ (5 mL),EDCI (187 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), DIEA (303 mg, 2.35mmol) were added under NH₃ at 0° C., and then stirred overnight. Thesolvent was removed under reduced pressure to give crude product, whichwas purified by preparative TLC to afford(±)-3-(2-amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide(110 mg, 56%). ¹H NMR (CDCl₃): δ=1.52-1.61 (m, 4H), 1.62-1.66 (m, 2H),1.68-1.70 (m, 2H), 1.75-1.76 (m, 2H), 1.78-1.80 (m, 1H), 1.82-1.85 (m,6H), 1.90-1.98 (m, 2H), 2.11-2.21 (m, 1H), 2.30-2.40 (m, 1H), 2.60-2.70(m, 1H), 2.80-2.88 (m, 1H), 2.95-3.15 (m, 2H), 3.65-3.75 (m, 2H),3.76-3.88 (m, 1H), 4.00 (s, 2H), 5.40-5.55 (d, 2H), 7.15-7.25 (m, 4H).

Example 128 1-Tert-butyl1′-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate

The title compound was prepared from tert-butylspiro[indoline-3,4′-piperidine]-1-carboxylate following a procedureanalogous to that described in Example 24 Step 2.

Example 129 1-Tert-butyl 1′-(2-adamantyl)5-fluorospiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate

The title compound was prepared from tert-butyl5-fluorospiro[indoline-3,4′-piperidine]-1-carboxylate following aprocedure analogous to that described in Example 24 Step 2.

Example 130 1-Tert-butyl 1′-(2-adamantyl)5-methylspiro[indoline-3,4′-piperidine]-1,1′-dicarboxylate

The title compound was prepared from tert-butyl5-methylspiro[indoline-3,4′-piperidine]-1-carboxylate following aprocedure analogous to that described in Example 24 Step 2.

Example 131(±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide

The title compound was prepared from(±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid following a procedure analogous to that described in Example 127except that 0.5 M NH₃ in dioxane was used in place of NH₃ gas.

Compounds names were generated with the assistance of ChemDraw® softwareversion 9.0 (Cambridgesoft, Cambridge, Mass., USA).

The following tables (I-VIII) indicate those compounds of the inventionthat can be prepared by the methods described herein.

TABLE I

Prophetic Example R^(8a) R⁴ Q R^(7a) 132 H H NH CONH₂ 133 H Me NH CONH₂134 H Boc NH CONH₂ 135 H MeOCO NH CONH₂ 136 H CH₃CO NH CONH₂ 137 Ht-BuCO NH CONH₂ 138 H MeNHCO NH CONH₂ 139 H t-BuNHCO NH CONH₂ 140 HMeSO₂ NH CONH₂ 141 H i-PrSO₂ NH CONH₂ 142 H MeNHSO₂ NH CONH₂ 143 H H OCONH₂ 144 H Me O CONH₂ 145 H MeOCO O CONH₂ 146 H CH₃CO O CONH₂ 147 Ht-BuCO O CONH₂ 148 H MeNHCO O CONH₂ 149 H t-BuNHCO O CONH₂ 150 H MeSO₂ OCONH₂ 151 H i-PrSO₂ O CONH₂ 152 H MeNHSO₂ O CONH₂ 153 F Me NH H 154 FBoc NH H 155 F t-BuCO NH H 156 F MeSO₂ NH H 157 F Me O H 158 F t-BuCO OH 159 F MeSO₂ O H 160 F H O CONH₂ 161 F Me O CONH₂ 162 F Boc O CONH₂ 163F CH₃CO O CONH₂ 164 F t-BuCO O CONH₂ 165 F MeSO₂ O CONH₂ 166 CF₃ H NH H167 CF₃ Me NH H 168 CF₃ Boc NH H 169 CF₃ CH₃CO NH H 170 CF₃ t-BuCO NH H171 CF₃ MeSO₂ NH H 172 CF₃ H O H 173 CF₃ Me O H 174 CF₃ Boc O H 175 CF₃CH₃CO O H 176 CF₃ t-BuCO O H 177 CF₃ MeSO₂ O H 178 CF₃ H O CONH₂ 179 CF₃Me O CONH₂ 180 CF₃ Boc O CONH₂ 181 CF₃ CH₃CO O CONH₂ 182 CF₃ t-BuCO OCONH₂ 183 CF₃ MeSO₂ O CONH₂ 184 CN H NH H 185 CN Me NH H 186 CN Boc NH H187 CN CH₃CO NH H 188 CN t-BuCO NH H 189 CN MeSO₂ NH H 190 CN H O H 191CN Me O H 192 CN Boc O H 193 CN CH₃CO O H 194 CN t-BuCO O H 195 CN MeSO₂O H 196 CN H O CONH₂ 197 CN Me O CONH₂ 198 CN Boc O CONH₂ 199 H H NH OH200 H Me NH OH 201 H Boc NH OH 202 H MeOCO NH OH 203 H CH₃CO NH OH 204 Ht-BuCO NH OH 205 H MeNHCO NH OH 206 H t-BuNHCO NH OH 207 H MeSO₂ NH OH208 H i-PrSO₂ NH OH 209 H MeNHSO₂ NH OH 210 H H O OH 211 H Me O OH 212 HBoc O OH 213 H MeOCO O OH 214 H CH₃CO O OH 215 H t-BuCO O OH 216 HMeNHCO O OH 217 H t-BuNHCO O OH 218 H MeSO₂ O OH 219 H i-PrSO₂ O OH 220H MeNHSO₂ O OH 221 H H NH CH₂OH 222 H Me NH CH₂OH 223 H Boc NH CH₂OH 224H MeOCO NH CH₂OH 225 H CH₃CO NH CH₂OH 226 H t-BuCO NH CH₂OH 227 H MeNHCONH CH₂OH 228 H t-BuNHCO NH CH₂OH 229 H MeSO₂ NH CH₂OH 230 H i-PrSO₂ NHCH₂OH 231 H MeNHSO₂ NH CH₂OH 232 H H O CH₂OH 233 H Me O CH₂OH 234 H BocO CH₂OH 235 H MeOCO O CH₂OH 236 H CH₃CO O CH₂OH 237 H t-BuCO O CH₂OH 238H MeNHCO O CH₂OH 239 H t-BuNHCO O CH₂OH 240 H MeSO₂ O CH₂OH 241 Hi-PrSO₂ O CH₂OH 242 H MeNHSO₂ O CH₂OH 243 H H NH SO₂Me 244 H Me NH SO₂Me245 H Boc NH SO₂Me 246 H MeOCO NH SO₂Me 247 H CH₃CO NH SO₂Me 248 Ht-BuCO NH SO₂Me 249 H MeNHCO NH SO₂Me 250 H t-BuNHCO NH SO₂Me 251 HMeSO₂ NH SO₂Me 252 H i-PrSO₂ NH SO₂Me 253 H MeNHSO₂ NH SO₂Me 254 H H OSO₂Me 255 H Me O SO₂Me 256 H Boc O SO₂Me 257 H MeOCO O SO₂Me 258 H CH₃COO SO₂Me 259 H t-BuCO O SO₂Me 260 H MeNHCO O SO₂Me 261 H t-BuNHCO O SO₂Me262 H MeSO₂ O SO₂Me 263 H i-PrSO₂ O SO₂Me 264 H MeNHSO₂ O SO₂Me 265 H HNH SO₂NH₂ 266 H Me NH SO₂NH₂ 267 H Boc NH SO₂NH₂ 268 H MeOCO NH SO₂NH₂269 H CH₃CO NH SO₂NH₂ 270 H t-BuCO NH SO₂NH₂ 271 H MeNHCO NH SO₂NH₂ 272H t-BuNHCO NH SO₂NH₂ 273 H MeSO₂ NH SO₂NH₂ 274 H i-PrSO₂ NH SO₂NH₂ 275 HMeNHSO₂ NH SO₂NH₂ 276 H H O SO₂NH₂ 277 H Me O SO₂NH₂ 278 H Boc O SO₂NH₂279 H MeOCO O SO₂NH₂ 280 H CH₃CO O SO₂NH₂ 281 H t-BuCO O SO₂NH₂ 282 HMeNHCO O SO₂NH₂ 283 H t-BuNHCO O SO₂NH₂ 284 H MeSO₂ O SO₂NH₂ 285 Hi-PrSO₂ O SO₂NH₂ 286 H MeNHSO₂ O SO₂NH₂

TABLE II

Prophetic Example R^(8a) R⁴ Q R^(7a) 287 H H NH CONH₂ 288 H Me NH CONH₂289 H Boc NH CONH₂ 290 H MeOCO NH CONH₂ 291 H CH₃CO NH CONH₂ 292 Ht-BuCO NH CONH₂ 293 H MeNHCO NH CONH₂ 294 H t-BuNHCO NH CONH₂ 295 HMeSO₂ NH CONH₂ 296 H i-PrSO₂ NH CONH₂ 297 H MeNHSO₂ NH CONH₂ 298 H H OCONH₂ 299 H Me O CONH₂ 300 H Boc O CONH₂ 301 H MeOCO O CONH₂ 302 H CH₃COO CONH₂ 303 H t-BuCO O CONH₂ 304 H MeNHCO O CONH₂ 305 H t-BuNHCO O CONH₂306 H MeSO₂ O CONH₂ 307 H i-PrSO₂ O CONH₂ 308 H MeNHSO₂ O CONH₂ 309 F HNH H 310 F Me NH H 311 F Boc NH H 312 F CH₃CO NH H 313 F t-BuCO NH H 314F MeSO₂ NH H 315 F H O H 316 F Me O H 317 F Boc O H 318 F CH₃CO O H 319F t-BuCO O H 320 F MeSO₂ O H 321 F H O CONH₂ 322 F Me O CONH₂ 323 F BocO CONH₂ 324 F CH₃CO O CONH₂ 325 F t-BuCO O CONH₂ 326 F MeSO₂ O CONH₂ 327CF₃ H NH H 328 CF₃ Me NH H 329 CF₃ Boc NH H 330 CF₃ CH₃CO NH H 331 CF₃t-BuCO NH H 332 CF₃ MeSO₂ NH H 333 CF₃ H O H 334 CF₃ Me O H 335 CF₃ BocO H 336 CF₃ CH₃CO O H 337 CF₃ t-BuCO O H 338 CF₃ MeSO₂ O H 339 CF₃ H OCONH₂ 340 CF₃ Me O CONH₂ 341 CF₃ Boc O CONH₂ 342 CF₃ CH₃CO O CONH₂ 343CF₃ t-BuCO O CONH₂ 344 CF₃ MeSO₂ O CONH₂ 345 CN H NH H 346 CN Me NH H347 CN Boc NH H 348 CN CH₃CO NH H 349 CN t-BuCO NH H 350 CN MeSO₂ NH H351 CN H O H 352 CN Me O H 353 CN Boc O H 354 CN CH₃CO O H 355 CN t-BuCOO H 356 CN MeSO₂ O H 357 CN H O CONH₂ 358 CN Me O CONH₂ 359 CN Boc OCONH₂ 360 H H NH OH 361 H Me NH OH 362 H Boc NH OH 363 H MeOCO NH OH 364H CH₃CO NH OH 365 H t-BuCO NH OH 366 H MeNHCO NH OH 367 H t-BuNHCO NH OH368 H MeSO₂ NH OH 369 H i-PrSO₂ NH OH 370 H MeNHSO₂ NH OH 371 H H O OH372 H Me O OH 373 H Boc O OH 374 H MeOCO O OH 375 H CH₃CO O OH 376 Ht-BuCO O OH 377 H MeNHCO O OH 378 H t-BuNHCO O OH 379 H MeSO₂ O OH 380 Hi-PrSO₂ O OH 381 H MeNHSO₂ O OH 382 H H NH CH₂OH 383 H Me NH CH₂OH 384 HBoc NH CH₂OH 385 H MeOCO NH CH₂OH 386 H CH₃CO NH CH₂OH 387 H t-BuCO NHCH₂OH 388 H MeNHCO NH CH₂OH 389 H t-BuNHCO NEI CH₂OH 390 H MeSO₂ NHCH₂OH 391 H i-PrSO₂ NH CH₂OH 392 H MeNHSO₂ NH CH₂OH 393 H H O CH₂OH 394H Me O CH₂OH 395 H Boc O CH₂OH 396 H MeOCO O CH₂OH 397 H CH₃CO O CH₂OH398 H t-BuCO O CH₂OH 399 H MeNHCO O CH₂OH 400 H t-BuNHCO O CH₂OH 401 HMeSO₂ O CH₂OH 402 H i-PrSO₂ O CH₂OH 403 H MeNHSO₂ O CH₂OH 404 H H NHSO₂Me 405 H Me NH SO₂Me 406 H Boc NH SO₂Me 407 H MeOCO NH SO₂Me 408 HCH₃CO NH SO₂Me 409 H t-BuCO NH SO₂Me 410 H MeNHCO NH SO₂Me 411 Ht-BuNHCO NH SO₂Me 412 H MeSO₂ NH SO₂Me 413 H i-PrSO₂ NH SO₂Me 414 HMeNHSO₂ NH SO₂Me 415 H H O SO₂Me 416 H Me O SO₂Me 417 H Boc O SO₂Me 418H MeOCO O SO₂Me 419 H CH₃CO O SO₂Me 420 H t-BuCO O SO₂Me 421 H MeNHCO OSO₂Me 422 H t-BuNHCO O SO₂Me 423 H MeSO₂ O SO₂Me 424 H i-PrSO₂ O SO₂Me425 H MeNHSO₂ O SO₂Me 426 H H NH SO₂NH₂ 427 H Me NH SO₂NH₂ 428 H Boc NHSO₂NH₂ 429 H MeOCO NH SO₂NH₂ 430 H CH₃CO NH SO₂NH₂ 431 H t-BuCO NHSO₂NH₂ 432 H MeNHCO NH SO₂NH₂ 433 H t-BuNHCO NH SO₂NH₂ 434 H MeSO₂ NHSO₂NH₂ 435 H i-PrSO₂ NH SO₂NH₂ 436 H MeNHSO₂ NH SO₂NH₂ 437 H H O SO₂NH₂438 H Me O SO₂NH₂ 439 H Boc O SO₂NH₂ 440 H MeOCO O SO₂NH₂ 441 H CH₃CO OSO₂NH₂ 442 H t-BuCO O SO₂NH₂ 443 H MeNHCO O SO₂NH₂ 444 H t-BuNHCO OSO₂NH₂ 445 H MeSO₂ O SO₂NH₂ 446 H i-PrSO₂ O SO₂NH₂ 447 H MeNHSO₂ OSO₂NH₂

TABLE III

Prophetic Example R^(8a) R⁴ Q R^(7a) 448 H H NH CONH₂ 449 H Me NH CONH₂450 H Boc NH CONH₂ 451 H MeOCO NH CONH₂ 452 H CH₃CO NH CONH₂ 453 Ht-BuCO NH CONH₂ 454 H MeNHCO NH CONH₂ 455 H t-BuNHCO NH CONH₂ 456 HMeSO₂ NH CONH₂ 457 H i-PrSO₂ NH CONH₂ 458 H MeNHSO₂ NH CONH₂ 459 H H OCONH₂ 460 H Me O CONH₂ 461 H Boc O CONH₂ 462 H MeOCO O CONH₂ 463 H CH₃COO CONH₂ 464 H t-BuCO O CONH₂ 465 H MeNHCO O CONH₂ 466 H t-BuNHCO O CONH₂467 H MeSO₂ O CONH₂ 468 H i-PrSO₂ O CONH₂ 469 H MeNHSO₂ O CONH₂ 470 F HNH H 471 F Me NH H 472 F Boc NH H 473 F CH₃CO NH H 474 F t-BuCO NH H 475F MeSO₂ NH H 476 F H O H 477 F Me O H 478 F Boc O H 479 F CH₃CO O H 480F t-BuCO O H 481 F MeSO₂ O H 482 F H O CONH₂ 483 F Me O CONH₂ 484 F BocO CONH₂ 485 F CH₃CO O CONH₂ 486 F t-BuCO O CONH₂ 487 F MeSO₂ O CONH₂ 488CF₃ H NH H 489 CF₃ Me NH H 490 CF₃ Boc NH H 491 CF₃ CH₃CO NH H 492 CF₃t-BuCO NH H 493 CF₃ MeSO₂ NH H 494 CF₃ H O H 495 CF₃ Me O H 496 CF₃ BocO H 497 CF₃ CH₃CO O H 498 CF₃ t-BuCO O H 499 CF₃ MeSO₂ O H 500 CF₃ H OCONH₂ 501 CF₃ Me O CONH₂ 502 CF₃ Boc O CONH₂ 503 CF₃ CH₃CO O CONH₂ 504CF₃ t-BuCO O CONH₂ 505 CF₃ MeSO₂ O CONH₂ 506 CN H NH H 507 CN Me NH H508 CN Boc NH H 509 CN CH₃CO NH H 510 CN t-BuCO NH H 511 CN MeSO₂ NH H512 CN H O H 513 CN Me O H 514 CN Boc O H 515 CN CH₃CO O H 516 CN t-BuCOO H 517 CN MeSO₂ O H 518 CN H O CONH₂ 519 CN Me O CONH₂ 520 CN Boc OCONH₂ 521 H H NH OH 522 H Me NH OH 523 H Boc NH OH 524 H MeOCO NH OH 525H CH₃CO NH OH 526 H t-BuCO NH OH 527 H MeNHCO NH OH 528 H t-BuNHCO NH OH529 H MeSO₂ NH OH 530 H i-PrSO₂ NH OH 531 H MeNHSO₂ NH OH 532 H H O OH533 H Me O OH 534 H Boc O OH 535 H MeOCO O OH 536 H CH₃CO O OH 537 Ht-BuCO O OH 538 H MeNHCO O OH 539 H t-BuNHCO O OH 540 H MeSO₂ O OH 541 Hi-PrSO₂ O OH 542 H MeNHSO₂ O OH 543 H H NH CH₂OH 544 H Me NH CH₂OH 545 HBoc NH CH₂OH 546 H MeOCO NH CH₂OH 547 H CH₃CO NH CH₂OH 548 H t-BuCO NHCH₂OH 549 H MeNHCO NH CH₂OH 550 H t-BuNHCO NH CH₂OH 551 H MeSO₂ NH CH₂OH552 H i-PrSO₂ NH CH₂OH 553 H MeNHSO₂ NH CH₂OH 554 H H O CH₂OH 555 H Me OCH₂OH 556 H Boc O CH₂OH 557 H MeOCO O CH₂OH 558 H CH₃CO O CH₂OH 559 Ht-BuCO O CH₂OH 560 H MeNHCO O CH₂OH 561 H t-BuNHCO O CH₂OH 562 H MeSO₂ OCH₂OH 563 H i-PrSO₂ O CH₂OH 564 H MeNHSO₂ O CH₂OH 565 H H NH SO₂NH₂ 566H Me NH SO₂NH₂ 567 H Boc NH SO₂NH₂ 568 H MeOCO NH SO₂NH₂ 569 H CH₃CO NHSO₂NH₂ 570 H t-BuCO NH SO₂NH₂ 571 H MeNHCO NH SO₂NH₂ 572 H t-BuNHCO NHSO₂NH₂ 573 H MeSO₂ NH SO₂NH₂ 574 H i-PrSO₂ NH SO₂NH₂ 575 H MeNHSO₂ NHSO₂NH₂ 576 H H O SO₂NH₂ 577 H Me O SO₂NH₂ 578 H Boc O SO₂NH₂ 579 H MeOCOO SO₂NH₂ 580 H CH₃CO O SO₂NH₂ 581 H t-BuCO O SO₂NH₂ 582 H MeNHCO OSO₂NH₂ 583 H t-BuNHCO O SO₂NH₂ 584 H MeSO₂ O SO₂NH₂ 585 H i-PrSO₂ OSO₂NH₂ 586 H MeNHSO₂ O SO₂NH₂

TABLE IV

Prophetic Example R⁴ Q R^(7a) 587 CO₂H NH CONH₂ 588 CH₂CO₂H NH CONH₂ 589CH₂CH₂CO₂H NH CONH₂ 590 CH₂CH₂CH₂CO₂H NH CONH₂ 591 CO₂Me NH CONH₂ 592CH₂CO₂Me NH CONH₂ 593 CH₂CH₂CO₂Me NH CONH₂ 594 CH₂CH₂CH₂CO₂Me NH CONH₂595 C(CH₃)₂CO₂H NH CONH₂ 596 C(CH₃)₂CO₂Me NH CONH₂ 597 CH₂(5-tetrazolyl)NH CONH₂ 598 CH₂CONHSO₂Me NH CONH₂ 599 CO₂H O CONH₂ 600 CH₂CH₂CO₂H OCONH₂ 601 CH₂CH₂CH₂CO₂H O CONH₂ 602 CO₂Me O CONH₂ 603 CH₂CO₂Me O CONH₂604 CH₂CH₂CO₂Me O CONH₂ 605 CH₂CH₂CH₂CO₂Me O CONH₂ 606 C(CH₃)₂CO₂H OCONH₂ 607 C(CH₃)₂CO₂Me O CONH₂ 608 CH₂(5-tetrazolyl) O CONH₂ 609CH₂CONHSO₂Me O CONH₂ 610 CO₂H NH OH 611 CH₂CO₂H NH OH 612 CH₂CH₂CO₂H NHOH 613 CH₂CH₂CH₂CO₂H NH OH 614 CO₂Me NH OH 615 CH₂CO₂Me NH OH 616CH₂CH₂CO₂Me NH OH 617 CH₂CH₂CH₂CO₂Me NH OH 618 C(CH₃)₂CO₂H NH OH 619C(CH₃)₂CO₂Me NH OH 620 CH₂(5-tetrazolyl) NH OH 621 CH₂CONHSO₂Me NH OH622 CO₂H NH CH₂OH 623 CH₂CO₂H NH CH₂OH 624 CH₂CH₂CO₂H NH CH₂OH 625CH₂CH₂CH₂CO₂H NH CH₂OH 626 CO₂Me NH CH₂OH 627 CH₂CO₂Me NH CH₂OH 628CH₂CH₂CO₂Me NH CH₂OH 629 CH₂CH₂CH₂CO₂Me NH CH₂OH 630 C(CH₃)₂CO₂H NHCH₂OH 631 C(CH₃)₂CO₂Me NH CH₂OH 632 CH₂(5-tetrazolyl) NH CH₂OH 633CH₂CONHSO₂Me NH CH₂OH 634 CO₂H O SO₂NH₂ 635 CH₂CH₂CO₂H O SO₂NH₂ 636CH₂CH₂CH₂CO₂H O SO₂NH₂ 637 CO₂NH₂ O SO₂NH₂ 638 CH₂CONH₂ O SO₂NH₂ 639CH₂CH₂CO₂NH₂ O SO₂NH₂ 640 CH₂CH₂CH₂CONH₂ O SO₂NH₂ 641 C(CH₃)₂CO₂H OSO₂NH₂ 642 C(CH₃)₂CONH₂ O SO₂NH₂ 643 CH₂(5-tetrazolyl) O SO₂NH₂ 644CH₂CONHSO₂Me O SO₂NH₂ 645 CO₂H NH SO₂NH₂ 646 CH₂CH₂CO₂H NH SO₂NH₂ 647CH₂CH₂CH₂CO₂H NH SO₂NH₂ 648 CO₂NH₂ NH SO₂NH₂ 649 CH₂CONH₂ NH SO₂NH₂ 650CH₂CH₂CO₂NH₂ NH SO₂NH₂ 651 CH₂CH₂CH₂CONH₂ NH SO₂NH₂ 652 C(CH₃)₂CO₂H NHSO₂NH₂ 653 C(CH₃)₂CONH₂ NH SO₂NH₂ 654 CH₂(5-tetrazolyl) NH SO₂NH₂ 655CH₂CONHSO₂Me NH SO₂NH₂ 656 CO₂H O SO₂Me 657 CH₂CH₂CO₂H O SO₂Me 658CH₂CH₂CH₂CO₂H O SO₂Me 659 CO₂NH₂ O SO₂Me 660 CH₂CONH₂ O SO₂Me 661CH₂CH₂CO₂NH₂ O SO₂Me 662 CH₂CH₂CH₂CONH₂ O SO₂Me 663 C(CH₃)₂CO₂H O SO₂Me664 C(CH₃)₂CONH₂ O SO₂Me 665 CH₂(5-tetrazolyl) O SO₂Me 666 CH₂CONHSO₂MeO SO₂Me 667 CO₂H NH SO₂Me 668 CH₂CH₂CO₂H NH SO₂Me 669 CH₂CH₂CH₂CO₂H NHSO₂Me 670 CO₂NH₂ NH SO₂Me 671 CH₂CONH₂ NH SO₂Me 672 CH₂CH₂CO₂NH₂ NHSO₂Me 673 CH₂CH₂CH₂CONH₂ NH SO₂Me 674 C(CH₃)₂CO₂H NH SO₂Me 675C(CH₃)₂CONH₂ NH SO₂Me 676 CH₂(5-tetrazolyl) NH SO₂Me 677 CH₂CONHSO₂Me NHSO₂Me

TABLE V

Prophetic Example R⁵ Q R^(7a) 678 H NH H 679 CO₂H NH H 680 CO₂Me NH H681 CH₂CO₂H NH H 682 CH₂CO₂Me NH H 683 H O H 684 CO₂H O H 685 CO₂Me O H686 CH₂CO₂H O H 687 CH₂CO₂Me O H 688 H NH CONH₂ 689 CO₂H NH CONH₂ 690CO₂Me NH CONH₂ 691 CH₂CO₂H NH CONH₂ 692 CH₂CO₂Me NH CONH₂ 693 H O CONH₂694 CO₂H O CONH₂ 695 CO₂Me O CONH₂ 696 CH₂CO₂H O CONH₂ 697 CH₂CO₂Me OCONH₂ 698 H NH OH 699 CO₂H NH OH 700 CO₂Me NH OH 701 CH₂CO₂H NH OH 702CH₂CO₂Me NH OH 703 H O OH 704 CO₂H O OH 705 CO₂Me O OH 706 CH₂CO₂H O OH707 CH₂CO₂Me O OH 708 H NH CH₂OH 709 CO₂H NH CH₂OH 710 CO₂Me NH CH₂OH711 CH₂CO₂H NH CH₂OH 712 CH₂CO₂Me NH CH₂OH 713 H O CH₂OH 714 CO₂H OCH₂OH 715 CO₂Me O CH₂OH 716 CH₂CO₂H O CH₂OH 717 CH₂CO₂Me O CH₂OH 718 HNH SO₂Me 719 CO₂H NH SO₂Me 720 CONH₂ NH SO₂Me 721 CH₂CO₂H NH SO₂Me 722CH₂CONH₂ NH SO₂Me 723 H O SO₂Me 724 CO₂H O SO₂Me 725 CONH₂ O SO₂Me 726CH₂CO₂H O SO₂Me 727 CH₂CONH₂ O SO₂Me 728 H NH SO₂NH₂ 729 CO₂H NH SO₂NH₂730 CONH₂ NH SO₂NH₂ 731 CH₂CO₂H NH SO₂NH₂ 732 CH₂CONH₂ NH SO₂NH₂ 733 H OSO₂NH₂ 734 CO₂H O SO₂NH₂ 735 CONH₂ O SO₂NH₂ 736 CH₂CO₂H O SO₂NH₂ 737CH₂CONH₂ O SO₂NH₂

TABLE VI

Prophetic Example R⁵ Q R^(7a) 738 H NH H 739 CO₂H NH H 740 CO₂Me NH H741 CH₂CO₂H NH H 742 CH₂CO₂Me NH H 743 H O H 744 CO₂H O H 745 CO₂Me O H746 CH₂CO₂H O H 747 CH₂CO₂Me O H 748 H NH CONH₂ 749 CO₂H NH CONH₂ 750CO₂Me NH CONH₂ 751 CH₂CO₂H NH CONH₂ 752 CH₂CO₂Me NH CONH₂ 753 H O CONH₂754 CO₂H O CONH₂ 755 CO₂Me O CONH₂ 756 CH₂CO₂H O CONH₂ 757 CH₂CO₂Me OCONH₂ 758 H NH OH 759 CO₂H NH OH 760 CO₂Me NH OH 761 CH₂CO₂H NH OH 762CH₂CO₂Me NH OH 763 H O OH 764 CO₂H O OH 765 CO₂Me O OH 766 CH₂CO₂H O OH767 CH₂CO₂Me O OH 768 H NH CH₂OH 769 CO₂H NH CH₂OH 770 CO₂Me NH CH₂OH771 CH₂CO₂H NH CH₂OH 772 CH₂CO₂Me NH CH₂OH 773 H O CH₂OH 774 CO₂H OCH₂OH 775 CO₂Me O CH₂OH 776 CH₂CO₂H O CH₂OH 777 CH₂CO₂Me O CH₂OH 778 HNH SO₂Me 779 CO₂H NH SO₂Me 780 CONH₂ NH SO₂Me 781 CH₂CO₂H NH SO₂Me 782CH₂CONH₂ NH SO₂Me 783 H O SO₂Me 784 CO₂H O SO₂Me 785 CONH₂ O SO₂Me 786CH₂CO₂H O SO₂Me 787 CH₂CONH₂ O SO₂Me 788 H NH SO₂NH₂ 789 CO₂H NH SO₂NH₂790 CONH₂ NH SO₂NH₂ 791 CH₂CO₂H NH SO₂NH₂ 792 CH₂CONH₂ NH SO₂NH₂ 793 H OSO₂NH₂ 794 CO₂H O SO₂NH₂ 795 CONH₂ O SO₂NH₂ 796 CH₂CO₂H O SO₂NH₂ 797CH₂CONH₂ O SO₂NH₂

TABLE VII

Prophetic Example R⁵ Q R^(7a) 798 H NH H 799 CO₂H NH H 800 CO₂Me NH H801 CH₂CO₂H NH H 802 CH₂CO₂Me NH H 803 H O H 804 CO₂H O H 805 CO₂Me O H806 CH₂CO₂H O H 807 CH₂CO₂Me O H 808 H NH CONH₂ 809 CO₂H NH CONH₂ 810CO₂Me NH CONH₂ 811 CH₂CO₂H NH CONH₂ 812 CH₂CO₂Me NH CONH₂ 813 H O CONH₂814 CO₂H O CONH₂ 815 CO₂Me O CONH₂ 816 CH₂CO₂H O CONH₂ 817 CH₂CO₂Me OCONH₂ 818 H NH OH 819 CO₂H NH OH 820 CO₂Me NH OH 821 CH₂CO₂H NH OH 822CH₂CO₂Me NH OH 823 H O OH 824 CO₂H O OH 825 CO₂Me O OH 826 CH₂CO₂H O OH827 CH₂CO₂Me O OH 828 H NH CH₂OH 829 CO₂H NH CH₂OH 830 CO₂Me NH CH₂OH831 CH₂CO₂H NH CH₂OH 832 CH₂CO₂Me NH CH₂OH 833 H O CH₂OH 834 CO₂H OCH₂OH 835 CO₂Me O CH₂OH 836 CH₂CO₂H O CH₂OH 837 CH₂CO₂Me O CH₂OH 838 HNH SO₂Me 839 CO₂H NH SO₂Me 840 CONH₂ NH SO₂Me 841 CH₂CO₂H NH SO₂Me 842CH₂CONH₂ NH SO₂Me 843 H O SO₂Me 844 CO₂H O SO₂Me 845 CONH₂ O SO₂Me 846CH₂CO₂H O SO₂Me 847 CH₂CONH₂ O SO₂Me 848 H NH SO₂NH₂ 849 CO₂H NH SO₂NH₂850 CONH₂ NH SO₂NH₂ 851 CH₂CO₂H NH SO₂NH₂ 852 CH₂CONH₂ NH SO₂NH₂ 853 H OSO₂NH₂ 854 CO₂H O SO₂NH₂ 855 CONH₂ O SO₂NH₂ 856 CH₂CO₂H O SO₂NH₂ 857CH₂CONH₂ O SO₂NH₂

TABLE VIII

Prophetic Example R⁴ Q R^(7a) R^(8b) 858 CO₂H NH H Me 859 CO₂H O H Me860 CH₂CO₂H O H Me 861 CO₂H NH CONH₂ Me 862 CH₂CO₂H NH CONH₂ Me 863 CO₂HO CONH₂ Me 864 CH₂CO₂H O CONH₂ Me 865 CO₂H NH H cyclopropyl 866 CH₂CO₂HNH H cyclopropyl 867 CO₂H O H cyclopropyl 868 CH₂CO₂H O H cyclopropyl869 CO₂H NH CONH₂ cyclopropyl 870 CH₂CO₂H NH CONH₂ cyclopropyl 871 CO₂HO CONH₂ cyclopropyl 872 CH₂CO₂H O CONH₂ cyclopropyl 873 CO₂H NH H Et 874CH₂CO₂H NH H Et 875 CO₂H O H Et 876 CH₂CO₂H O H Et 877 CO₂H NH CONH₂ Et878 CH₂CO₂H NH CONH₂ Et 879 CO₂H O CONH₂ Et 880 CH₂CO₂H O CONH₂ Et 881CO₂H NH H CF₃ 882 CH₂CO₂H NH H CF₃ 883 CO₂H O H CF₃ 884 CH₂CO₂H O H CF₃885 CO₂H NH CONH₂ CF₃ 886 CH₂CO₂H NH CONH₂ CF₃ 887 CO₂H O CONH₂ CF₃ 888CH₂CO₂H O CONH₂ CF₃ 889 CO₂H NH H Cl 890 CH₂CO₂H NH H Cl 891 CO₂H O H Cl892 CH₂CO₂H O H Cl 893 CO₂H NH CONH₂ Cl 894 CH₂CO₂H NH CONH₂ Cl 895 CO₂HO CONH₂ Cl 896 CH₂CO₂H O CONH₂ Cl 897 CO₂H NH SO₂NH₂ Cl 898 CH₂CO₂H NHSO₂NH₂ Cl 899 CO₂H O SO₂NH₂ Cl 900 CH₂CO₂H O SO₂NH₂ Cl 901 CO₂H NH SO₂MeCl 902 CH₂CO₂H NH SO₂Me Cl 903 CO₂H O SO₂Me Cl 904 CH₂CO₂H O SO₂Me Cl905 CONH₂ NH H Cl 906 CH₂CONH₂ NH H Cl 907 CONH₂ O H Cl 908 CH₂CONH₂ O HCl 909 CONH₂ NH CONH₂ Cl 910 CH₂CONH₂ NH CONH₂ Cl 911 CONH₂ O CONH₂ Cl912 CH₂CONH₂ O CONH₂ Cl 913 CONH₂ NH SO₂NH₂ Cl 914 CH₂CONH₂ NH SO₂NH₂ Cl915 CONH₂ O SO₂NH₂ Cl 916 CH₂CONH₂ O SO₂NH₂ Cl 917 CONH₂ NH SO₂Me Cl 918CH₂CONH₂ NH SO₂Me Cl 919 CONH₂ O SO₂Me Cl 920 CH₂CONH₂ O SO₂Me Cl

Biological Test Example 1

The inhibition of purified 11β-HSD1 by compounds of Formula I or I* ismeasured using a Scintillation Proximity Assay. All reactions arecarried out at room temperature in 96 well flexible Microbeta reactionplates. First, 1 μL of a 0.1 mM solution of a compound of Formula I orI* is mixed in DMSO diluted in half-log increments (8 points) startingat 1 μM final concentration. To this dot is added 50 μL of substratesolution (50 mM HEPES, pH 7.4, 100 mM KCl, 5 mM NaCl, 2 mM MgCl₂containing 20 μM ³H cortisone, 1 mM NADPH). After a 10 minuteincubation, 50 μL of enzyme solution containing 20 nM recombinant11β-HSD1 (expressed in E. coli, and affinity purified) is added. Thereaction is then incubated for 90 minutes, and stopped by adding 50 μlof SPA bead mix (18-β-glycyrrhetinic acid, 10 μM final, 5 mg/ml proteinA coated YSi SPA beads, and 1 μg/ml α-cortisol antibody (East CoastBiologics)). The plate is shaken for 120 minutes, and the radioactivitycorresponding to ³H cortisol is measured on a Wallac Microbeta.

Biological Test Example 2

The inhibition of a microsomal preparation of 11β-HSD1 by compounds ofthe invention is measured essentially as previously described (K. Solly,et al., High-Throughput Screening of 11-Beta-HydroxysteroidDehydrogenase Type 1 in Scintillation Proximity Assay Format, Assay DrugDev Technol 3 (2005) 377-384). All reactions are carried out at roomtemperature in 96 well clear flexible PET Microbeta plates(PerkinElmer). First, 49 μl of substrate solution (50 mM HEPES, pH 7.4,100 mM KCl, 5 mM NaCl, 2 mM MgCl₂, 2 mM NADPH and 160 nM [³H]cortisone(1 Ci/mmol)) is mixed in 1 μl, of a test compound in DMSO diluted inhalf-log increments (8 points) starting at 0.1 mM. After a 10 minutepre-incubation, 50 μL of enzyme solution containing microsomes isolatedfrom CHO cells overexpressing human 11β-HSD1 (10-20 μg/ml of totalprotein) is added, and the plates are then incubated for 90 minutes atroom temperature. The reaction is stopped by adding 50 μl of the SPAbeads suspension containing 10 nM 18β-glycyrrhetinic acid, 5 mg/mlprotein A coated YSi SPA beads (GE Healthcare) and 3.3 μg/ml ofanti-cortisol antibody (East Coast Biologics) in Superblock buffer(Bio-Rad). The plates are then shaken for 120 minutes at roomtemperature, and the SPA signal corresponding to [³H]cortisol ismeasured on a Microbeta plate reader.

Biological Test Example 3

The inhibition of 11β-HSD1 by compounds of this invention is measured inwhole cells as follows. Cells for the assay can be obtained from twosources: fully differentiated human omental adipocytes from Zen-Bio,Inc.; and human omental pre-adipocytes from Lonza Group Ltd.Pre-differentiated omental adipocytes from Zen-Bio Inc. are purchased in96-well plates and used in the assay at least two weeks afterdifferentiation from precursor preadipocytes. Zen-Bio induceddifferentiation of pre-adipocytes by supplementing medium withadipogenic and lipogenic hormones (human insulin, dexamethasone,isobutylmethylxanthine and PPAR-γ agonist). The cells are maintained infull adipocyte medium (DMEM/Ham's F-12 (1:1, v/v), HEPES pH 7.4, fetalbovine serum, penicillin, streptomycin and Amphotericin B, supplied byZen-Bio, Inc.) at 37° C., 5% CO₂.

Pre-adipocytes (purchased from Lonza Group Ltd.) are placed in culturein Preadipocyte Growth Medium-2 supplemented with fetal bovine serum,penicillin, and streptomycin (supplied by Lonza) at 37° C., CO₂.Pre-adipocytes are differentiated by the addition of insulin,dexamethasone, indomethacin and isobutyl-methylxanthine (supplied byLonza) to the Preadipocyte Growth Medium-2. Cells are then exposed tothe differentiating factors for 7 days, at which point the cells aredifferentiated and ready for the assay. One day before running theassay, the differentiated omental adipocytes are transferred into serum-and phenol-red-free medium for overnight incubation. The assay isperformed in a total volume of 200 μL. The cells are pre-incubated withserum-free, phenol-red-free medium containing 0.1% (v/v) of DMSO andvarious concentrations of the test compounds at least 1 h before[³H]cortisone in ethanol (50 Ci/mmol, ARC, Inc.) is added to achieve afinal concentration of cortisone of 100 nM. The cells are then incubatedfor 3-4 hrs at 37° C., 5% CO₂. Negative controls are incubated withoutradioactive substrate and receive the same amount of [³H]cortisone atthe end of the incubation. Formation of [³H]cortisol is monitored byanalyzing 25 μL of each supernatant in a scintillation proximity assay(SPA). (Solly, K., et al., Assay Drug Dev. Technol. 2005, 3, 377-384).

The inhibition of 11β-HSD1 by compounds of Formulae I, Ia, Ib, Ic, Id,Ie, If, Ig, Ih, or Ii, in whole cells is measured as follows. Omentaladipocytes cultured in 96-well plates (purchased from Zen-Bio, Inc.) areused at least two weeks after differentiation from precursorpreadipocytes started in medium supplemented with adipogenic andlipogenic hormones (human insulin, dexamethasone, isobutylmethylxanthineand PPARγ agonist). The cells are maintained in full adipocyte medium(DMEM/Ham's F-12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum,penicillin, streptomycin and Amphotericin B, supplied by Zen-Bio, Inc.)at 37° C., 5% CO₂ and then transferred into serum-free, phenol red freemedium for overnight incubation. The assay is performed in a totalvolume of 200 μL. The cells are pre-incubated with serum-free, phenolred free medium containing 0.1% (v/v) of DMSO and various concentrationsof compounds of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii, forat least 1 h before [³H]cortisone in ethanol (50 Ci/mmol, ARC, Inc.) isadded to achieve final concentration of cortisone of 100 nM. The cellsare then incubated for 3-4 h at 37° C., 5% CO₂. Negative controls areincubated without radioactive substrate and receive the same amount of[³H]cortisone at the end of the incubation. Formation of [³H]cortisol ismonitored by analyzing 25 μL of each supernatant in scintillationproximity assay (SPA). (Solly, K.; et al., Assay Drug Dev. Technol.2005, 3, 377-384).

Biological Test Biological Test Example Example 1^(a) Example 2^(a)  1++ nt  2 ++ nt  3 ++ ++  4 ++ nt  5 Isomer 1 ++ nt  5 Isomer 2 ++ nt  6Isomer 1 + nt  6 Isomer 2 ++ nt  7 ++ nt  8 + nt  9 + nt  10 + nt  11 ++nt  12 ++ nt  13 + nt  14 + nt  15 ++ nt  16 ++ nt  17 + nt  18 + nt  19++ nt  20 ++ nt  21 ++ nt  22 ++ nt  23 ++ ++  24 ++ nt  25 ++ nt  26 ++nt  27 nt ++  27, Step 1 Product nt ++  27, Step 2 Product nt ++  28 nt++  29 ++ nt  30 ++ ++  31 ++ ++  32 nt ++  33 nt ++  34 nt ++  35 nt ++ 36 nt ++  37 nt ++  38 nt ++  39 nt ++  40 nt ++  41 nt ++  42 nt ++ 43 nt ++  43 Isomer 1 nt ++  43 Isomer 2 nt ++  44 nt ++  45 nt ++  46nt ++  47 nt ++  48 nt ++  49 nt ++  50 nt ++  51 nt ++  52 nt ++  53 nt++  54 nt ++  55 nt ++  56 nt ++  57 nt ++  58 nt ++  59 nt ++  60 nt ++ 61 nt ++  62 nt ++  63 nt ++  63 Isomer 1 nt ++  63 Isomer 2 nt ++  64nt ++  65 nt ++  66 nt ++  67 nt ++  68 nt ++  69 nt ++  70 nt ++  71 nt++  72 nt +  73 nt ++  74 nt ++  74 Isomer 1 nt ++  74 Isomer 2 nt ++ 74 Isomer 3 nt ++  75 Isomer 1 nt ++  75 Isomer 2 nt ++  75 Isomer 3nt +  76 nt +  77 nt ++  78 nt ++  79 nt ++  80 nt +  81 nt ++  82 nt + 83 nt ++  84 ++ ++  85 nt ++  86 nt ++  86, Step 1 Product nt ++  87 nt++  87, Step 1 Product nt ++  88 nt ++  88, Step 1 Product nt nt  89nt +  90 nt ++  91 nt ++  92 nt ++  93 nt ++  94 nt ++  95 + ++  96 nt++  97 nt ++  98 nt +  99 nt + 100 nt ++ 101 Isomer 1 nt ++ 101 Isomer 2nt ++ 102 nt ++ 103 nt ++ 103, Step 1 Product nt ++ 104 nt ++ 104, Step1 Product nt nt 105 nt ++ 105, Step 1 Product nt nt 106 nt ++ 107 nt ++108 nt ++ 109 nt ++ 110 nt ++ 111 nt ++ 112 nt ++ 113 nt ++ 114 nt ++115 nt ++ 115 Isomer 1 nt ++ 115 Isomer 2 nt ++ 116 nt ++ 117 nt ++ 118nt ++ 119 nt ++ 120 nt ++ 121 nt ++ 122 nt ++ 123 nt ++ 124 nt ++ 125 nt++ 126 nt ++ 127 nt ++ 128 + nt 129 + nt 130 + nt 131 nt ++ ^(a)++ meansIC₅₀ < 50 nM, + means IC₅₀ = 50 nM to 1000 nM; nt = not tested.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication or patent application were specificallyand individually designated as having been incorporated by reference. Itis understood that the examples and embodiments described herein are forillustrative purposes only, and it will be appreciated that theinvention is susceptible to modification, variation and change withoutdeparting from the proper scope or fair meaning of the appended claims.

What is claimed is:
 1. A compound represented by the followingstructural formula:

wherein: M, X and Y are independently C; n=0, 1, or 2; s=1; t=1 or 2;u=0, 1, 2 or 3; R⁴ is A-(5-tetrazolyl), A-(cycloalkyl), A-(heteroaryl),A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶, A-CONHSO₂R⁶,A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl, alkenyl, cycloalkyl,heteroaryl, heterocyclyl, aryl, or arylalkyl; R³ and R⁵ areindependently hydrogen, A-(5-tetrazolyl), A-(cycloalkyl),A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶, A-CON(R⁶)₂, A-COR⁶,A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂, A-C≡N, alkyl,alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, or arylalkyl,wherein the alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl,A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl) or arylalkylgroups represented by R³-R⁵ are optionally and independently substitutedwith 1-3 groups independently selected from the group consisting ofhalogen, hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; p3, p4 or p5,respectively, is 1; A is a single bond, (C₁-C₆)alkylene,(C₂-C₆)alkenylene, (C₁-C₅)alkyleneCH═,C(O)(C₀-C₃)alkylene(C₃-C₆)cycloalkyl(C₀-C₃)alkylene,C(O)(C₁-C₆)alkylene, C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene,S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkylene(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶; R⁶ is hydrogen, (C₁-C₁₀)alkyl,halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, (R⁶)₂N(C₁-C₁₀)alkyl, aryl orarylalkyl, wherein the aryl and arylalkyl groups are optionallysubstituted with up to three groups independently selected from halogen,hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or N(R⁶)₂ is aheterocyclyl group containing at least one nitrogen atom selected fromW¹-W⁷:

Q is O or NR⁶; and R⁷ is a saturated C₉-C₁₂ tricycloalkyl—which isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of R⁶, heteroaryl, oxo-substituted heteroaryl,amino-substituted heteroaryl, heterocyclyl, oxo-substitutedheterocyclyl, halogen, hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶,CH₂CONHR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶,SO₂R⁶, NHCOR⁶, NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; R⁸ isindependently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1, represented by the formula:

wherein: n=0, 1 or 2; s=1; t=1 or 2; u=0, 1, 2 or 3; R⁸ is independentlyselected from halogen, cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂ and NR⁶SO₂R⁶; R⁴ is COOR⁶,CH₂COOR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂, COR⁶, SO₂R⁶, CONHSO₂R⁶, CH₂CONHSO₂R⁶,alkyl, cycloalkyl, heteroaryl, aryl or arylalkyl; R³ and R⁵ areindependently H, COOR⁶, CH₂COOR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂, COR⁶, SO₂R⁶,CONHSO₂R⁶, CH₂CONHSO₂R⁶, alkyl, cycloalkyl, heteroaryl, aryl orarylalkyl, wherein the cyclohexyl, heteroaryl, aryl or arylalkyl groupsrepresented by R³-R⁵ are optionally and independently substituted with1-3 groups independently selected from the group consisting of halogen,cyano, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, CONH₂ and NR⁶SO₂R⁶; R⁶ ishydrogen, (C₁-C₄)alkyl, aryl or arylalkyl; Q is O or NR⁶; and R⁷ is asaturated C₉-C₁₂ tricycloalkyl which is optionally substituted with 1-3substituents independently selected from the group consisting of R⁶,heteroaryl, oxo-substituted heteroaryl, amino-substituted heteroaryl,heterocyclyl, oxo-substituted heterocyclyl, halogen, hydroxy,hydroxymethyl, C(NOH)NH₂, CONHR⁶, CH₂CONHR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂,SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶, SO₂R⁶, NHCOR⁶, NR⁶COR⁶, NHCO₂R⁶,NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.
 3. Thecompound of claim 2, where n is
 0. 4. The compound of claim 3, where sis 1 and t is
 2. 5. The compound of claim 4, where R⁴ is COOR⁶ orCH₂COOR⁶.
 6. The compound of claim 3, where R⁵ is H, R⁶ is hydrogen or(C₁-C₄)alkyl Q is O, NH or NR⁶; and R⁷ is 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-(methylsulfonyl)-4-adamantyl,1-(aminosulfonyl)-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl.
 7. The compound according to claim 2,wherein Q is O or NH.
 8. The compound according to claim 2, wherein Q isO and R⁷ is selected from the group consisting of 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl, and1-carbamoyl-4-adamantyl.
 9. The compound according to claim 2, wherein Qis NH and R⁷ is selected from the group consisting of 2-adamantyl,1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl, and1-carbamoyl-4-adamantyl.
 10. The compound of claim 1, represented by theformula:

or an enantiomer, diastereomer, geometrical isomer or pharmaceuticallyacceptable salt thereof.
 11. A compound according to claim 10, wherein:R⁴ is A-(5 tetrazolyl), A-COOR⁶, ACON(R⁶)₂, A-CONHSO₂R⁶ or alkyl,wherein the alkyl is optionally and independently substituted with 1-3groups independently selected from the group consisting of hydroxy,cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, —CONH₂, —SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and—NR⁶SO₂OR⁶; A is a bond or (C₁-C₃)alkylene; s=1; t=2; u=1; Q is NH or O;R⁷ is 2-adamantyl, 1-hydroxy-4-adamantyl, 1-hydroxymethyl-4-adamantyl,1-carbamoyl-4-adamantyl, 1-(methylsulfonyl)-4-adamantyl,1-(aminosulfonyl)-4-adamantyl, 1-bicyclo[2.2.2]octyl,1-carbamoyl-4-bicyclo[2.2.2]octyl, 9-bicyclo[3.3.1]nonyl or3-carbamoyl-9-bicyclo[3.3.1]nonyl; and R⁸ is halogen or methyl.
 12. Apharmaceutical composition comprising an effective amount of a compoundaccording of claim 1, and a pharmaceutically acceptable carrier.
 13. Thecompound of claim 1, wherein the compound is of a formula selected from:(±)-2-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Methyl2-(1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;2-(1′-((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-1′((2-Adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylicacid; (±)-Ethyl1′-(cyclohexylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-carboxylate;(±)-2-Adamantyl3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;2-(1′((2-Adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-2-Adamantyl3-(2-(methylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;(±)-Ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(7-Bromo-1′((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-N-(2-Adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-3-(Cyanomethyl)-N-cyclohexyl-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-3-((1H-Tetrazol-5-yl)methyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(1′-((2-Adamantyl)carbamoyl)-7-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(1′-((2-Adamantyl)carbamoyl)-4-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(1′-((2-Adamantyl)carbamoyl)-7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Ethyl2-(1′-((2-adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(1′-((2-Adamantyl)carbamoyl)-5-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(1′-((2-Adamantyl)carbamoyl)-5-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-methoxy-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(1′-((2-Adamantyl)carbamoyl)-6-fluoro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid; (±)-Ethyl2-(7-bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate;(±)-2-(7-Bromo-1′-((1-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(7-Bromo-1′((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(6-Methyl-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(5-Methyl-1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;2-(7-Bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoicacid; (±)-Ethyl2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate;(±)-2-(7-Bromo-1′((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoicacid; (±)-2-Adamantyl7-bromo-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;(±)-7-Bromo-N-(2-adamantyl)-3-(2-(methylsulfonamido)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-2-Adamantyl3-(2-(dimethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;2-(1′-((1-(3,5-Dimethoxybenzylcarbamoyl)4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;2-(1′-((1-Carbamoyl-4adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;2-(7-Bromo-1′-(1-fluoro-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;2-(7-Bromo-1′-(1-hydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;(±)-2-(7-Bromo-1′-(1,7-dihydroxy-4-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;2-(1′-((1-(Benzylcarbamoyl)-4-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)aceticacid;7-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(piperazin-1-yl)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(2-(dimethylamino)ethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(methyl(2-(methylamino)ethyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(2-(dimethylamino)ethyl)(methyl)amino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(3-(dimethylamino)propylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(4-(dimethylamino)butylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-oxo-2-(2-(piperazin-1-yl)ethylamino)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;7-Bromo-N-(2-adamantyl)-3-(2-(2-(4-methylpiperazin-1-yl)ethylamino)-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-7-Bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-7-Bromo-N-(2-adamantyl)-3-(1-hydroxy-2-methylpropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-2-Adamantyl3-(aminomethyl)-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;(±)-2-Adamantyl7-bromo-3-((dimethylamino)methyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate;(±)-7-Bromo-N-(2-adamantyl)-3-(2-morpholinoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;(±)-3-(2-Amino-2-oxoethyl)-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;and(±)-3-(2-amino-2-oxoethyl)-7-bromo-N-(2-adamantyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide;or a pharmaceutically acceptable salt thereof.
 14. The compound of claim1, represented by the formula:

wherein: s=1; t=1 or 2; u=0, 1,2 or 3; R⁴ is A-(5-tetrazolyl),A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl), A-(aryl), A-COOR⁶,A-CON(R⁶)₂, A-COR⁶, A-SO₂R⁶, A-CONHSO₂R⁶, A-CONHSO₂OR⁶, A-CONHSO₂N(R⁶)₂,A-C≡N, alkyl, alkenyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, orarylalkyl, wherein the alkyl, alkenyl, cycloalkyl, heteroaryl,heterocyclyl, aryl, A-(cycloalkyl), A-(heteroaryl), A-(heterocyclyl),A-(aryl) or arylalkyl groups represented by R⁴ are optionally andindependently substituted with 1-3 groups independently selected fromthe group consisting of halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CONH₂, —SO₂R⁶, —NR⁶SO₂R⁶,—NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; A is a single bond, (C₁-C₆)alkylene,(C₂-C₆)alkenylene, (C₁-C₅)alkyleneCH═,C(O)(C₀-C₃)alkylene(C₃-C₆)cycloalkyl(C₀-C₃)alkylene,C(O)(C₁-C₆)alkylene, C(O)(C₂-C₆)alkenylene, S(O)₂(C₁-C₆)alkylene,S(O)₂(C₂-C₆)alkenylene, orS(O)₂(C₀-C₃)alkylene(C₃-C₆)cycloalkyl(C₀-C₃)alkylene, each optionallysubstituted with up to 4 groups, R⁶; R⁶ is hydrogen, (C₁-C₁₀)alkyl,halo(C₁-C₁₀)alkyl, hydroxy(C₁-C₁₀)alkyl, (R⁶)₂N(C₁-C₁₀)alkyl, aryl orarylalkyl, wherein the aryl and arylalkyl groups are optionallysubstituted with up to three groups independently selected from halogen,hydroxy, cyano, —N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂,—SO₂R⁶, —NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or N(R⁶)₂ is aheterocyclyl group containing at least one nitrogen atom selected fromW¹-W⁷:

Q is O or NR⁶; and R⁷ is a saturated C₉-C₁₂ tricycloalkyl which isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of R⁶, heteroaryl, oxo-substituted heteroaryl,amino-substituted heteroaryl, heterocyclyl, oxo-substitutedheterocyclyl, halogen, hydroxy, hydroxy(C₁-C₆)alkyl, C(NOH)NH₂, CONHR⁶,CH₂CONHR⁶, CON(R⁶)₂, CH₂CON(R⁶)₂, SO₂NHR⁶, SO₂N(R⁶)₂, CO₂R⁶, CH₂CO₂R⁶,SO₂R⁶, NHCOR⁶, NR⁶COR⁶, NHCO₂R⁶, NR⁶CO₂R⁶, NHSO₂R⁶, and NR⁶SO₂R⁶; R⁸ isindependently selected from halogen, hydroxy, cyano, —N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁶, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkoxy, CON(R⁶)₂, SO₂N(R⁶)₂, —SO₂R⁶,—NR⁶SO₂R⁶, —NR⁶SO₂N(R⁶)₂ and —NR⁶SO₂OR⁶; or an enantiomer, diastereomer,geometrical isomer or pharmaceutically acceptable salt thereof.